rs586592

Positions:

• chr11-103187397-C-G
• chr11-103187397-C-T

Variant summary

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

The NM_001377.3(DYNC2H1):​c.6951C>G​(p.His2317Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H2317H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71

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.6951C>G	p.His2317Gln	missense_variant	43/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.6951C>G	p.His2317Gln	missense_variant	43/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6951C>G	p.His2317Gln	missense_variant	43/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.6951C>G	p.His2317Gln	missense_variant	43/89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;.;.
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	.;D;.;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.0	D;.;.;D
REVEL	Benign	0.24
Sift	Benign	0.070	T;.;.;T
Sift4G	Benign	0.085	T;.;.;T
Polyphen		0.95	P;P;D;D
Vest4		0.84
MutPred		0.58		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.59
MPC		0.25
ClinPred		0.98	D
GERP RS		2.1
Varity_R		0.48
gMVP		0.71

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: rs586592; hg19: chr11-103058126;