rs780855765

Positions:

• chr11-103184963-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001080463.2(DYNC2H1):​c.6545G>A​(p.Cys2182Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.54

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
• PP5: Variant 11-103184963-G-A is Pathogenic according to our data. Variant chr11-103184963-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446602.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22345015). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.6545G>A	p.Cys2182Tyr	missense_variant	41/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.6545G>A	p.Cys2182Tyr	missense_variant	41/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6545G>A	p.Cys2182Tyr	missense_variant	41/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.6545G>A	p.Cys2182Tyr	missense_variant	41/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+50544G>A		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000649323.1	c.*4090G>A		3_prime_UTR_variant, NMD_transcript_variant	39/51			ENSP00000497581

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248428 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D;.;.
Eigen	Benign	-0.032
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	.;T;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;M;M
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.3	D;.;.;D
REVEL	Benign	0.11
Sift	Uncertain	0.011	D;.;.;D
Sift4G	Uncertain	0.021	D;.;.;D
Polyphen		0.40	B;B;P;P
Vest4		0.79
MutPred		0.41		Gain of disorder (P = 0.0612);Gain of disorder (P = 0.0612);Gain of disorder (P = 0.0612);Gain of disorder (P = 0.0612);
MVP		0.39
MPC		0.22
ClinPred		0.89	D
GERP RS		3.9
Varity_R		0.39
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs780855765; hg19: chr11-103055692;