rs1555061228

Positions:

• chr11-103186491-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001377.3(DYNC2H1):​c.6883T>C​(p.Cys2295Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.36

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 11-103186491-T-C is Pathogenic according to our data. Variant chr11-103186491-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446552.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.6883T>C	p.Cys2295Arg	missense_variant	42/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.6883T>C	p.Cys2295Arg	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.6883T>C	p.Cys2295Arg	missense_variant	42/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.6883T>C	p.Cys2295Arg	missense_variant	42/89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.8	M;M;M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-8.8	D;.;.;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;.;.;D
Sift4G	Uncertain	0.0050	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MutPred		0.70		Gain of MoRF binding (P = 0.0165);Gain of MoRF binding (P = 0.0165);Gain of MoRF binding (P = 0.0165);Gain of MoRF binding (P = 0.0165);
MVP		0.74
MPC		0.50
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.90

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: rs1555061228; hg19: chr11-103057220;