NM_001038603.3:c.1504-2579C>A

Variant names:

• chr5-69437871-C-A
• rs2561183
• NM_001038603.3:c.1504-2579C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001038603.3(MARVELD2):​c.1504-2579C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 151,912 control chromosomes in the GnomAD database, including 18,847 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (18847 hom., cov: 31)
• Consequence: MARVELD2 NM_001038603.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.333
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARVELD2	NM_001038603.3	c.1504-2579C>A		intron_variant	Intron 5 of 6	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10	c.1504-2579C>A		intron_variant	Intron 5 of 6	1	NM_001038603.3	ENSP00000323264.5

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75557 AN: 151792 Hom.: 18841 Cov.: 31

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.489

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75611 AN: 151912 Hom.: 18847 Cov.: 31 AF XY: 0.505 AC XY: 37466 AN XY: 74254

African (AFR) AF: 0.480 AC: 19856 AN: 41402

American (AMR) AF: 0.533 AC: 8132 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1766 AN: 3466

East Asian (EAS) AF: 0.485 AC: 2502 AN: 5160

South Asian (SAS) AF: 0.535 AC: 2578 AN: 4816

European-Finnish (FIN) AF: 0.586 AC: 6189 AN: 10556

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32902 AN: 67950

Other (OTH) AF: 0.493 AC: 1042 AN: 2112

Alfa AF: 0.490 Hom.: 10457

Bravo AF: 0.490

Asia WGS AF: 0.511 AC: 1779 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs2561183; hg19: chr5-68733698; COSMIC: COSV57780035;