chr11-103125195-T-G

Position:

• chr11-103125195-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The ENST00000375735.7(DYNC2H1):​c.1757T>G​(p.Val586Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DYNC2H1 ENST00000375735.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.64

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 11-103125195-T-G is Pathogenic according to our data. Variant chr11-103125195-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220042.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.1757T>G	p.Val586Gly	missense_variant	12/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.1757T>G	p.Val586Gly	missense_variant	12/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.1757T>G	p.Val586Gly	missense_variant	12/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.1757T>G	p.Val586Gly	missense_variant	12/89	1	NM_001377.3	ENSP00000364887	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461352 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2015

This variant has not been published in the literature and is not present in population databases. This sequence change replaces valine with glycine at codon 586 of the DYNC2H1 protein (p.Val586Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. For these reasons, this variant has been classified as Pathogenic. This variant was found in trans with a pathogenic variant in DYNC2H1 (c.2702+1G>A) in the proband of this family who was diagnosed with asphyxiating thoracic dystrophy. The phase of the two variants were confirmed through parental testing. Although this c.1757T>G (p.Val586Gly) variant has not been reported in the literature, a mutation in the neighboring codon c.1759C>T (p.Arg587Cys) has been reported to segregate with short-rib polydactyly syndrome in a single consanguineous family (PMID: 19361615). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 02, 2023

Variant summary: DYNC2H1 c.1757T>G (p.Val586Gly) results in a non-conservative amino acid change located in the Dynein heavy chain, tail domain (IPR013594) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248368 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1757T>G in individuals affected with Short-rib thoracic dysplasia and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic reporting its presence as a compound heterozygous genotype in an individual diagnosed with asphyxiating thoracic dystrophy while another submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 06, 2018

The DYNC2H1 c.1757T>G; p.Val586Gly variant (rs864622357), to our knowledge, is not reported in the medical literature but is described as pathogenic by one laboratory in ClinVar (Variation ID: 220042). It is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 586 is highly conserved and computational algorithms (SIFT, PolyPhen-2) predict this variant to be deleterious. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;.;D;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;.;T;D;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Uncertain	0.0088	D
MutationAssessor	Uncertain	2.6	.;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.7	.;D;D;.;.;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;D;D;.;.;D
Sift4G	Pathogenic	0.0010	.;D;D;.;.;D
Polyphen		1.0	.;D;D;D;D;D
Vest4		0.56, 0.62, 0.57
MutPred		0.75		Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);
MVP		0.76
MPC		0.43
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.82

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: rs864622357; hg19: chr11-102995924;