rs1555061008

Positions:

• chr11-103186302-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000375735.7(DYNC2H1):​c.6694G>C​(p.Asp2232His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D2232D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2H1 ENST00000375735.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.6694G>C	p.Asp2232His	missense_variant	42/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.6694G>C	p.Asp2232His	missense_variant	42/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6694G>C	p.Asp2232His	missense_variant	42/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.6694G>C	p.Asp2232His	missense_variant	42/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+51883G>C		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000649323.1	c.*4239G>C		3_prime_UTR_variant, NMD_transcript_variant	40/51			ENSP00000497581

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Jeune thoracic dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

This sequence change replaces aspartic acid with histidine at codon 2232 of the DYNC2H1 protein (p.Asp2232His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DYNC2H1-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	.;D;.;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.7	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.6	D;.;.;D
REVEL	Benign	0.29
Sift	Benign	0.030	D;.;.;D
Sift4G	Uncertain	0.058	T;.;.;T
Polyphen		0.99	D;D;D;D
Vest4		0.73
MutPred		0.43		Gain of methylation at R2235 (P = 0.0529);Gain of methylation at R2235 (P = 0.0529);Gain of methylation at R2235 (P = 0.0529);Gain of methylation at R2235 (P = 0.0529);
MVP		0.60
MPC		0.26
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.64

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: rs1555061008; hg19: chr11-103057031;