rs2434507

Variant names:

• chr5-69429983-A-G
• rs2434507
• NM_001038603.3:c.1183-2544A>G

Variant summary

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

The NM_001038603.3(MARVELD2):​c.1183-2544A>G 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 151,658 control chromosomes in the GnomAD database, including 18,813 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 (18813 hom., cov: 30)
• Consequence: MARVELD2 NM_001038603.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.543
• Publications: 5 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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARVELD2	NM_001038603.3	c.1183-2544A>G		intron_variant	Intron 3 of 6	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10	c.1183-2544A>G		intron_variant	Intron 3 of 6	1	NM_001038603.3	ENSP00000323264.5

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75433 AN: 151538 Hom.: 18807 Cov.: 30

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.455

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: 75488 AN: 151658 Hom.: 18813 Cov.: 30 AF XY: 0.504 AC XY: 37364 AN XY: 74074

African (AFR) AF: 0.480 AC: 19844 AN: 41340

American (AMR) AF: 0.533 AC: 8107 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1755 AN: 3468

East Asian (EAS) AF: 0.493 AC: 2530 AN: 5134

South Asian (SAS) AF: 0.536 AC: 2576 AN: 4808

European-Finnish (FIN) AF: 0.585 AC: 6119 AN: 10464

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32874 AN: 67916

Other (OTH) AF: 0.493 AC: 1039 AN: 2106

Alfa AF: 0.497 Hom.: 2456

Bravo AF: 0.490

Asia WGS AF: 0.515 AC: 1793 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.9
DANN	Benign	0.76
PhyloP100		-0.54
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: rs2434507; hg19: chr5-68725810; COSMIC: COSV57779961;