rs765998830

Positions:

• chr11-103200059-C-T

Variant summary

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

The NM_001080463.2(DYNC2H1):​c.8102C>T​(p.Ala2701Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000309 in 1,583,296 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.91

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 4 ACMG points.

• PM1: In a region_of_interest AAA 4 (size 246) in uniprot entity DYHC2_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.8102C>T	p.Ala2701Val	missense_variant	50/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.8102C>T	p.Ala2701Val	missense_variant	50/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.8102C>T	p.Ala2701Val	missense_variant	50/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.8102C>T	p.Ala2701Val	missense_variant	50/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+65640C>T		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*5626C>T		3_prime_UTR_variant, NMD_transcript_variant	48/51

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000293 AC: 42 AN: 1431132 Hom.: 0 Cov.: 30 AF XY: 0.0000282 AC XY: 20 AN XY: 708822

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000144

Gnomad4 ASJ exome AF: 0.00110

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000457

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000887 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000251 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 01, 2017	The p.Ala2701Val variant has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. However, it has been reported to ClinVar (Variation ID 302066). It is listed in the Genome Aggregation Database (gnomAD) with overall allele frequency of 0.0065 percent (identified on 2 out of 30,970 chromosomes). The alanine at position 2701 is moderately conserved (considering 11 species) and computational analyses of the effects of the p.Ala2701Val variant on protein structure and function predict a mixed effect (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Ala2701Val variant with certainty. -

Jeune thoracic dystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change replaces alanine with valine at codon 2701 of the DYNC2H1 protein (p.Ala2701Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs765998830, ExAC 0.05%). This variant has not been reported in the literature in individuals affected with DYNC2H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 302066). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Asphyxiating thoracic dystrophy 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	.;T;.;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.6	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.3	D;.;.;D
REVEL	Uncertain	0.32
Sift	Benign	0.12	T;.;.;T
Sift4G	Benign	0.12	T;.;.;T
Polyphen		0.99	D;D;D;D
Vest4		0.81
MutPred		0.61		Loss of catalytic residue at A2701 (P = 0.1503);Loss of catalytic residue at A2701 (P = 0.1503);Loss of catalytic residue at A2701 (P = 0.1503);Loss of catalytic residue at A2701 (P = 0.1503);
MVP		0.66
MPC		0.29
ClinPred		0.91	D
GERP RS		6.2
Varity_R		0.44
gMVP		0.79

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: rs765998830; hg19: chr11-103070788;