11-103177728-A-G

Position:

• chr11-103177728-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001080463.2(DYNC2H1):​c.6047A>G​(p.Tyr2016Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,613,562 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7 B:1
• Conservation: PhyloP100: 4.38

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a region_of_interest AAA 2 (size 223) in uniprot entity DYHC2_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_001080463.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.027013153).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.6047A>G	p.Tyr2016Cys	missense_variant	38/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.6047A>G	p.Tyr2016Cys	missense_variant	38/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6047A>G	p.Tyr2016Cys	missense_variant	38/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.6047A>G	p.Tyr2016Cys	missense_variant	38/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+43309A>G		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*3592A>G		3_prime_UTR_variant, NMD_transcript_variant	36/51

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000785 AC: 195 AN: 248512 Hom.: 0 AF XY: 0.000712 AC XY: 96 AN XY: 134822

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00140 AC: 2050 AN: 1461318 Hom.: 2 Cov.: 31 AF XY: 0.00138 AC XY: 1005 AN XY: 726942

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74432

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000922

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000525 AC: 2

ESP6500EA AF: 0.00134 AC: 11

ExAC AF: 0.000612 AC: 74

EpiCase AF: 0.00153

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DYNC2H1 p.Tyr2016Cys variant was identified in 1 of 304 proband chromosomes (frequency: 0.0033) in a Caucasian neonate with short-rib polydactyly syndrome (Zhang_2018_PMID: 29068549), and in 1 out of 8 proband chromosomes from families with recurrent pregnancy loss (Qiao_2016_PMID: 26826164). The variant was also identified in dbSNP (ID: rs200190291) and in ClinVar (classified as a VUS by Invitae, GeneDx and ARUP and as pathogenic by the Dan Cohn lab at UCLA) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 221 of 279910 chromosomes at a frequency of 0.00079 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: Latino in 47 of 35140 chromosomes (freq: 0.001338), European (non-Finnish) in 151 of 128142 chromosomes (freq: 0.001178), Other in 8 of 7106 chromosomes (freq: 0.001126), African in 10 of 24174 chromosomes (freq: 0.000414) and European (Finnish) in 5 of 25018 chromosomes (freq: 0.0002); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Tyr2016 residue is not 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26826164, 29068549) -

Asphyxiating thoracic dystrophy 3 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 11, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2023	The DYNC2H1 c.6047A>G; p.Tyr2016Cys variant (rs200190291) has been described in the compound heterozygous state in one family with recurrent early pregnancy loss and in one individual with short-rib thoracic dysplasia type IV (Qiao 2016, Zhang 2018). It is reported in ClinVar (Variation ID: 216490) and is observed in the general population at an overall frequency of 0.079% (221/279,910 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.047). Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Qiao Y et al. Whole exome sequencing in recurrent early pregnancy loss. Mol Hum Reprod. 2016 May;22(5):364-72. PubMed: 26826164. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PubMed: 29068549. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 08, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Type IV short rib polydactyly syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 07, 2023

Variant summary: DYNC2H1 c.6047A>G (p.Tyr2016Cys) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 248512 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (0.00078 vs 0.0025), allowing no conclusion about variant significance. c.6047A>G has been reported in the literature in at least one individual affected with skeletal ciliopathy (Zhang_2017) and one family tested for whole exome sequencing in recurrent early pregnancy loss (Qiao_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Short-rib thoracic dysplasia. 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, 26826164). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; five submitters classified it as uncertain significance, one classified it as likkely benign, and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jeune thoracic dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;.;.
Eigen	Benign	0.064
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.11	N;N;N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N;.;.;N
REVEL	Benign	0.047
Sift	Benign	0.16	T;.;.;T
Sift4G	Benign	0.14	T;.;.;T
Polyphen		0.14	B;B;B;B
Vest4		0.37
MVP		0.56
MPC		0.080
ClinPred		0.027	T
GERP RS		5.5
Varity_R		0.10
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200190291; hg19: chr11-103048457; COSMIC: COSV62088248;