11-103199333-G-A

Variant names:

• chr11-103199333-G-A
• NM_001080463.2:c.7945G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001377.3(DYNC2H1):​c.7945G>A​(p.Gly2649Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest AAA 4 (size 246) in uniprot entity DYHC2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001377.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.7945G>A	p.Gly2649Ser	missense_variant	Exon 49 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.7945G>A	p.Gly2649Ser	missense_variant	Exon 49 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.7945G>A	p.Gly2649Ser	missense_variant	Exon 49 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.7945G>A	p.Gly2649Ser	missense_variant	Exon 49 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459780 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726170

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.8	M;M;M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.6	D;.;.;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.016	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.88
MutPred		0.59		Gain of phosphorylation at G2649 (P = 0.0809);Gain of phosphorylation at G2649 (P = 0.0809);Gain of phosphorylation at G2649 (P = 0.0809);Gain of phosphorylation at G2649 (P = 0.0809);
MVP		0.73
MPC		0.36
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.89
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-103070062;