rs1043384862

chr11-103165911-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001080463.2(DYNC2H1):c.4625C>T(p.Ala1542Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,493,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1542A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.62

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-103165911-C-T is Pathogenic according to our data. Variant chr11-103165911-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.4625C>T	p.Ala1542Val	missense_variant	31/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.4625C>T	p.Ala1542Val	missense_variant	31/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.4625C>T	p.Ala1542Val	missense_variant	31/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.4625C>T	p.Ala1542Val	missense_variant	31/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+31492C>T		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*2170C>T		3_prime_UTR_variant, NMD_transcript_variant	29/51

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 14 AN: 1341384 Hom.: 0 Cov.: 29 AF XY: 0.0000167 AC XY: 11 AN XY: 658790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000305

Gnomad4 SAS exome AF: 0.0000306

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:3

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	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Feb 24, 2015	This heterozygous variant in the DYNC2H1 gene (autosomal recessive transmission), inherited from the father, was present in a foetus who also harbours a second variant in the same gene inherited by the mother (compound heterozygosity). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2016

A novel A1542V variant that is likely pathogenic has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A1542V variant was not observed in approximately 5700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1542V 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. A missense variant in a nearby residue (Gln1537Arg) has been reported in the Human Gene Mutation Database in association with SRTD3 (Stenson et al., 2014), supporting the functional importance of this region of the protein. -

Jeune thoracic dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1542 of the DYNC2H1 protein (p.Ala1542Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with short-rib thoracic dysplasia with polydactyly (PMID: 27353043, 29068549, 35929941). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 373013). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYNC2H1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.7	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.1	D;.;.;D
REVEL	Benign	0.24
Sift	Uncertain	0.011	D;.;.;D
Sift4G	Uncertain	0.019	D;.;.;D
Polyphen		0.95	P;P;D;D
Vest4		0.87
MVP		0.72
MPC		0.20
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.59

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: rs1043384862; hg19: chr11-103036640;