rs189806840

Positions:

• chr11-103155439-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001080463.2(DYNC2H1):​c.3682C>A​(p.Leu1228Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,612,340 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:10 B:3
• Conservation: PhyloP100: 1.09

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008179843).
• BP6: Variant 11-103155439-C-A is Benign according to our data. Variant chr11-103155439-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238270.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.3682C>A	p.Leu1228Ile	missense_variant	25/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.3682C>A	p.Leu1228Ile	missense_variant	25/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.3682C>A	p.Leu1228Ile	missense_variant	25/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.3682C>A	p.Leu1228Ile	missense_variant	25/89	1	NM_001377.3	ENSP00000364887	P3

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 151872 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00162 AC: 402 AN: 247758 Hom.: 0 AF XY: 0.00169 AC XY: 227 AN XY: 134436

Gnomad AFR exome AF: 0.000909

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00233 AC: 3398 AN: 1460352 Hom.: 6 Cov.: 33 AF XY: 0.00231 AC XY: 1678 AN XY: 726444

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00343

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00180 AC: 274 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74286

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.00505

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00214 Hom.: 0

Bravo AF: 0.00229

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000545 AC: 2

ESP6500EA AF: 0.00171 AC: 14

ExAC AF: 0.00136 AC: 164

EpiCase AF: 0.00284

EpiControl AF: 0.00256

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:10 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 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, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DYNC2H1 p.Leu1228Ile variant was identified in 4 of 446 proband chromosomes (frequency: 0.00897) from individuals or families with short-rib polydactyly syndromes (SRPS), asphyxiating thoracic dystrophy (ATD) or Ellis van Creveld (EVC) syndrome (Schmidts_2013_PMID:23456818; Zhang_2018_PMID:29068549). The variant was also identified in dbSNP (ID: rs189806840), ClinVar (classified as likely benign by Invitae and GeneDx, a VUS by 4 labs and pathogenic by Dan Cohn Lab,University Of California Los Angeles) and LOVD 3.0. The variant was not identified in Cosmic. The variant was identified in control databases in 442 of 279018 chromosomes at a frequency of 0.001584 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 21 of 7080 chromosomes (freq: 0.002966), Latino in 104 of 35140 chromosomes (freq: 0.00296), European (non-Finnish) in 290 of 127576 chromosomes (freq: 0.002273), African in 22 of 24080 chromosomes (freq: 0.000914), European (Finnish) in 4 of 24956 chromosomes (freq: 0.00016) and Ashkenazi Jewish in 1 of 10318 chromosomes (freq: 0.000097), while the variant was not observed in the East Asian and South Asian populations. The p.Leu1228 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2018	This variant is associated with the following publications: (PMID: 29068549, 2687404, 23456818, 26874042, 30755392) -

Jeune thoracic dystrophy Pathogenic:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

Asphyxiating thoracic dystrophy 3 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 23, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 07, 2019	The DYNC2H1 c.3682C>A; p.Leu1228Ile variant (rs189806840) is reported in the literature in individuals affected with asphyxiating thoracic dysplasia, several of whom carried additional variants in the DYNC2H1 gene (Cossu 2016, Schmidts 2013, Zhang 2018). The p.Leu1228Ile variant is found in the Latino population with an overall allele frequency of 0.30% (104/35140 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 238270). The leucine at codon 1228 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Leu1228Ile variant is uncertain at this time. References: Cossu C et al. New mutations in DYNC2H1 and WDR60 genes revealed by whole-exome sequencing in two unrelated Sardinian families with Jeune asphyxiating thoracic dystrophy. Clin Chim Acta. 2016 Apr 1;455:172-80. Schmidts M et al. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. J Med Genet. 2013 May;50(5):309-23. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2024	Variant summary: DYNC2H1 c.3682C>A (p.Leu1228Ile) results in a conservative amino acid change located in the Dynein heavy chain, linker region (IPR013602) of 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 0.0016 in 247758 control chromosomes, predominantly at a frequency of 0.0028 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025). c.3682C>A has been reported in the literature in individuals affected with features of Short-rib thoracic dysplasia/Asphyxiating thoracic dystrophy (Zhang_2018, Schmitds_2013, Cossu_2016, Cloney_2022), and some of these individuals had a (likely) pathogenic variants in trans, although in another case additional variants in the DYNC2H1 gene were also noted. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29068549, 34740920, 26874042, 23456818). ClinVar contains an entry for this variant (Variation ID: 238270). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Cough;C1850049:Clinodactyly of the 5th finger;C4023252:Anomalous origin of coronary artery from the pulmonary artery Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;.;D;.;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.0082	T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	.;N;.;.;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.012	.;D;.;.;D
Sift4G	Uncertain	0.018	.;D;.;.;D
Polyphen		0.99, 1.0	.;D;D;D;D
Vest4		0.53, 0.52
MVP		0.62
MPC		0.36
ClinPred		0.023	T
GERP RS		-1.0
Varity_R		0.35
gMVP		0.38

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: rs189806840; hg19: chr11-103026168;