NM_001386795.1:c.112G>C

Variant names:

• chr18-34766005-G-C
• rs200256996
• NM_001386795.1:c.112G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001386795.1(DTNA):​c.112G>C​(p.Ala38Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A38T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.20

Genes affected

DTNA (HGNC:3057): (dystrobrevin alpha) The protein encoded by this gene belongs to the dystrobrevin subfamily of the dystrophin family. This protein is a component of the dystrophin-associated protein complex (DPC), which consists of dystrophin and several integral and peripheral membrane proteins, including dystroglycans, sarcoglycans, syntrophins and alpha- and beta-dystrobrevin. The DPC localizes to the sarcolemma and its disruption is associated with various forms of muscular dystrophy. Mutations in this gene are associated with left ventricular noncompaction with congenital heart defects. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ENSG00000268873 (HGNC:58208):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNA	NM_001386795.1	c.112G>C	p.Ala38Pro	missense_variant	Exon 3 of 23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6	c.112G>C	p.Ala38Pro	missense_variant	Exon 3 of 23	5	NM_001386795.1	ENSP00000405819.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.6	H;H;H;.;.;.;.;H;H;H;H;H;H;H;.;H;H;H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.3	D;.;D;.;.;.;.;.;D;D;.;.;.;D;.;.;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;.;D;.;.;.;.;.;D;D;.;.;.;D;.;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;P;.;.;.;.;.;.;.;.;D;D;D;.;.;D;D
Vest4		0.92
MutPred		0.91		Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);.;Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);.;Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);Gain of glycosylation at A38 (P = 0.0384);
MVP		0.90
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200256996; hg19: chr18-32345969;