rs397514636

chr11-103191565-C-T

Variant summary

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

The NM_001080463.2(DYNC2H1):c.7486C>T(p.Pro2496Ser) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P2496P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.82

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, 0.871
• PP5: Variant 11-103191565-C-T is Pathogenic according to our data. Variant chr11-103191565-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 40069.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.7486C>T	p.Pro2496Ser	missense_variant	46/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.7486C>T	p.Pro2496Ser	missense_variant	46/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.7486C>T	p.Pro2496Ser	missense_variant	46/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.7486C>T	p.Pro2496Ser	missense_variant	46/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+57146C>T		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*5031C>T		3_prime_UTR_variant, NMD_transcript_variant	44/51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.2	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.2	D;.;.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.010	D;.;.;D
Sift4G	Uncertain	0.015	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.93
MutPred		0.60		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.70
MPC		0.39
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.47
gMVP		0.81

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: rs397514636; hg19: chr11-103062294;