rs751030969

chr11-103170226-C-T

Variant summary

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

The NM_001080463.2(DYNC2H1):c.5087C>T(p.Thr1696Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,611,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1696T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.90

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, 0.891
• PP5: Variant 11-103170226-C-T is Pathogenic according to our data. Variant chr11-103170226-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446616.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr11-103170226-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.5087C>T	p.Thr1696Met	missense_variant	33/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.5087C>T	p.Thr1696Met	missense_variant	33/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.5087C>T	p.Thr1696Met	missense_variant	33/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.5087C>T	p.Thr1696Met	missense_variant	33/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+35807C>T		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*2632C>T		3_prime_UTR_variant, NMD_transcript_variant	31/51

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD3 exomes AF: 0.0000244 AC: 6 AN: 246386 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 133648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1459718 Hom.: 0 Cov.: 30 AF XY: 0.0000537 AC XY: 39 AN XY: 726056

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.0000582 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1696 of the DYNC2H1 protein (p.Thr1696Met). This variant is present in population databases (rs751030969, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of short-rib thoracic dysplasia with or without polydactyly (PMID: 29068549, 29096039). ClinVar contains an entry for this variant (Variation ID: 446616). 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) performed at Invitae indicates that this missense variant is expected to disrupt DYNC2H1 protein function with a positive predictive value of 95%. 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. -
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	-	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

DYNC2H1: PM1, PM2, PP4:Moderate, PP3 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 27, 2023

Variant summary: DYNC2H1 c.5087C>T (p.Thr1696Met) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) and hydrolytic ATP-binding dynein motor region (IPR035699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5087C>T has been reported in the literature in at least two compound heterozygous individuals affected with Short-rib thoracic dysplasia (e.g., Zhang_2018, Stals_2018). 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: 29096039, 29068549). Two ClinVar submitters (evaluation after 2014) have classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	4.4	H;H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.8	D;.;.;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.83
MutPred		0.59		Loss of methylation at K1695 (P = 0.0329);Loss of methylation at K1695 (P = 0.0329);Loss of methylation at K1695 (P = 0.0329);Loss of methylation at K1695 (P = 0.0329);
MVP		0.77
MPC		0.39
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.81

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: rs751030969; hg19: chr11-103040955; COSMIC: COSV62104951;