chr11-103153376-G-T

Position:

• chr11-103153376-G-T

Variant summary

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

The NM_001377.3(DYNC2H1):​c.3170G>T​(p.Arg1057Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000644 in 1,398,548 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.22

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.3170G>T	p.Arg1057Leu	missense_variant	22/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.3170G>T	p.Arg1057Leu	missense_variant	22/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.3170G>T	p.Arg1057Leu	missense_variant	22/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.3170G>T	p.Arg1057Leu	missense_variant	22/89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000190 AC: 3 AN: 158136 Hom.: 0 AF XY: 0.0000360 AC XY: 3 AN XY: 83320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000886

Gnomad SAS exome AF: 0.0000903

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000644 AC: 9 AN: 1398548 Hom.: 0 Cov.: 30 AF XY: 0.00000870 AC XY: 6 AN XY: 689716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.0000897

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000906 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;D;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;.;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	.;M;M;M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.8	.;D;.;.;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	.;D;.;.;D
Sift4G	Uncertain	0.0070	.;D;.;.;D
Polyphen		0.99, 0.99	.;D;D;D;D
Vest4		0.65, 0.66
MutPred		0.40		.;Loss of MoRF binding (P = 0.035);Loss of MoRF binding (P = 0.035);Loss of MoRF binding (P = 0.035);Loss of MoRF binding (P = 0.035);
MVP		0.48
MPC		0.39
ClinPred		0.81	D
GERP RS		5.6
Varity_R		0.43
gMVP		0.62

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: rs191381310; hg19: chr11-103024105;