rs137853026

Positions:

• chr11-103304601-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001377.3(DYNC2H1):​c.11263A>G​(p.Met3755Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,609,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:9 B:1
• Conservation: PhyloP100: 9.18

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a region_of_interest AAA 6 (size 215) in uniprot entity DYHC2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001377.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019730449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.11284A>G	p.Met3762Val	missense_variant	78/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.11263A>G	p.Met3755Val	missense_variant	77/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.11284A>G	p.Met3762Val	missense_variant	78/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.11263A>G	p.Met3755Val	missense_variant	77/89	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	c.2206-131342A>G		intron_variant		1		ENSP00000334021.7
DYNC2H1	ENST00000528670.5	n.442A>G		non_coding_transcript_exon_variant	5/17	5		ENSP00000433451.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000337 AC: 83 AN: 246608 Hom.: 0 AF XY: 0.000261 AC XY: 35 AN XY: 133850

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1457464 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 107 AN XY: 724976

Gnomad4 AFR exome AF: 0.00342

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000702

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000568

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74430

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000232 Hom.: 0

Bravo AF: 0.00117

ESP6500AA AF: 0.00295 AC: 11

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000389 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 12, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2017	The M3762V variant has been published in the homozygous state in two children affected with skeletal dysplasia born to consanguineous parents; however, these children were also homozygous for another variant in the DYNC2H1 gene (Dagoneau et al., 2009). The M3762V variant is observed in 35/9648 (0.36%) alleles from individuals of African background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M3762V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

Asphyxiating thoracic dystrophy 3 Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.039%). The evidence of pathogenicity is insufficient at this time. This variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with short-rib thoracic dysplasia 3 with or without polydactyly (MIM#613091). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (153 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated AAA6 region (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported by seven clinical laboratories as a VUS, and one as likely benign (ClinVar). It has also been reported as compound heterozygous in an individual with asphyxiating thoracic dystrophy (ATD), a fetus with skeletal dysplasia, and a fetus with ultrasound findings of short femur and humerus lengths (PMID: 29068549, Johnson, K. and Eason, J. (2018), ClinVar - personal communication). In addition, this variant has been reported as homozygous in two individuals with ATD, including one who also had a CEP57 variant and a composite phenotype (PMIDs: 23339108, 31943948). It has also been reported as homozygous in an individual with severe global developmental delay, axial hypotonia and limb spasticity, who is also homozygous for a SOD1 variant that was regarded as the genetic diagnosis (PMID: 34788402), and an individual who does not have DYNC2H1-related symptoms (ClinVar - personal communication). Furthermore, this variant has been reported in cis with p.(Met1991Leu) (PMIDs: 19442771, 33875766); however, these reports were not considered for the classification of this variant. (I) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated within an extended consanguineous family, however as another variant is present in cis, the evidence is inconclusive (PMID: 19442771). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, flagged submission	literature only	OMIM	May 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2019	The DYNC2H1 c.11284A>G; p.Met3762Val variant (rs137853026) is reported in the literature in the homozygous state in multiple individuals affected with asphyxiating thoracic dystrophy, although some of these individuals also carry other variants in cis (Baujat 2013, Dagoneau 2009, Zhang 2018). This variant is reported] in ClinVar (Variation ID: 6501), and is found in the African population with an allele frequency of 0.32% (78/24098 alleles) in the Genome Aggregation Database. The methionine at codon 3762 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the limited clinical and functional data, the significance of the p.Met3762Val variant is uncertain at this time. References: Baujat G et al. Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet. 2013 Feb;50(2):91-8. Dagoneau N et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009 May;84(5):706-11. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. -

Jeune thoracic dystrophy Pathogenic:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Pathogenic, flagged submission	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, flagged submission	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 13, 2024

Variant summary: DYNC2H1 c.11284A>G (p.Met3762Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 246608 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025), however no homozygotes were present. c.11284A>G has been reported in the literature in individuals affected with Short-rib thoracic dysplasia, including in a homozygous patient without any other reported variants (Baujat_2013) and in three homozygous patients who also carried other possibly causitive homozygous or heterozygous DYNC2H1 variants (Hammarsjo_2021, Dagoneau_2009, Zhang_2019). Additionally, the variant was reported in a patient with complex phenotype in a homozygous patient who also carried homozygous CEP57 c.915_925dup (p.Leu309Profs*9) who had features of both DYNC2H1 and CEP57-related disease. The current clinical evidence is not sufficient to prove the causitive relationship of the variant to disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 6501). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.2	M;M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.5	D;.;.;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.0090	D;.;.;D
Polyphen		0.69	P;P;D;D
Vest4		0.84
MVP		0.64
MPC		0.23
ClinPred		0.13	T
GERP RS		5.4
Varity_R		0.86
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137853026; hg19: chr11-103175330;