rs762588952

chr11-103192133-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001080463.2(DYNC2H1):c.7577T>G(p.Ile2526Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000071 in 1,549,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2526V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.91

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 14) in uniprot entity DYHC2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-103192133-T-G is Pathogenic according to our data. Variant chr11-103192133-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-103192133-T-G is described in Lovd as [Pathogenic]. Variant chr11-103192133-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.7577T>G	p.Ile2526Ser	missense_variant	47/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.7577T>G	p.Ile2526Ser	missense_variant	47/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.7577T>G	p.Ile2526Ser	missense_variant	47/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.7577T>G	p.Ile2526Ser	missense_variant	47/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+57714T>G		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*5101T>G		3_prime_UTR_variant, NMD_transcript_variant	45/51

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152120 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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000644 AC: 9 AN: 1397070 Hom.: 0 Cov.: 30 AF XY: 0.00000725 AC XY: 5 AN XY: 689780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000837

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

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: 0.0000943

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000169 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2

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	-	- -

DYNC2H1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2023

The DYNC2H1 c.7577T>G variant is predicted to result in the amino acid substitution p.Ile2526Ser. This variant has been reported in fetuses affected with short rib-polydactyly syndrome (Ellard et al 2015. PubMed ID: 24961629; Table S2 in Zhang W et al 2017. PubMed ID: 29068549). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Based on the available evidence, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Benign	0.039
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;.;.;N
REVEL	Pathogenic	0.69
Sift	Benign	0.051	T;.;.;T
Sift4G	Uncertain	0.040	D;.;.;D
Polyphen		0.0010	B;B;B;B
Vest4		0.93
MutPred		0.70		Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);
MVP		0.46
MPC		0.095
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.35
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs762588952; hg19: chr11-103062862;