NM_001038603.3:c.58G>C

Variant names:

• chr5-69419443-G-C
• rs745712719
• NM_001038603.3:c.58G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001038603.3(MARVELD2):​c.58G>C​(p.Asp20His) 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. 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. D20N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.75
• Publications: 0 publications found

Genes affected

MARVELD2 (HGNC:26401): (MARVEL domain containing 2) The protein encoded by this gene is a membrane protein found at the tight junctions between epithelial cells. The encoded protein helps establish epithelial barriers such as those in the organ of Corti, where these barriers are required for normal hearing. Defects in this gene are a cause of deafness autosomal recessive type 49 (DFNB49). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

MARVELD2 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 49

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2827133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARVELD2	NM_001038603.3	c.58G>C	p.Asp20His	missense_variant	Exon 2 of 7	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10	c.58G>C	p.Asp20His	missense_variant	Exon 2 of 7	1	NM_001038603.3	ENSP00000323264.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.0088	.;T;T;T;.;T;T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	.;.;.;T;T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M;.;.;.
PhyloP100		3.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	.;N;.;.;N;D;N;N
REVEL	Benign	0.086
Sift	Uncertain	0.0010	.;D;.;.;D;D;D;D
Sift4G	Uncertain	0.052	.;T;.;.;T;D;T;T
Polyphen		0.99	D;D;D;D;D;.;.;.
Vest4		0.23, 0.21, 0.24
MutPred		0.16		Gain of catalytic residue at D20 (P = 0.0222);Gain of catalytic residue at D20 (P = 0.0222);Gain of catalytic residue at D20 (P = 0.0222);Gain of catalytic residue at D20 (P = 0.0222);Gain of catalytic residue at D20 (P = 0.0222);Gain of catalytic residue at D20 (P = 0.0222);Gain of catalytic residue at D20 (P = 0.0222);Gain of catalytic residue at D20 (P = 0.0222);
MVP		0.78
MPC		0.074
ClinPred		0.94	D
GERP RS		4.7
PromoterAI		0.018	Neutral
Varity_R		0.089
gMVP		0.20
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs745712719; hg19: chr5-68715270;