chr5-69437818-G-C

Variant names:

• chr5-69437818-G-C
• rs2561182
• NM_001038603.3:c.1504-2632G>C

Variant summary

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

The NM_001038603.3(MARVELD2):​c.1504-2632G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 151,974 control chromosomes in the GnomAD database, including 17,400 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 0.48 (17400 hom., cov: 31)
• Consequence: MARVELD2 NM_001038603.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.438
• Publications: 7 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=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001038603.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	NM_001038603.3	MANE Select	c.1504-2632G>C		intron	N/A	NP_001033692.2
	MARVELD2	NM_001244734.2		c.1468-2632G>C		intron	N/A	NP_001231663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	ENST00000325631.10	TSL:1 MANE Select	c.1504-2632G>C		intron	N/A	ENSP00000323264.5
	MARVELD2	ENST00000454295.6	TSL:1	c.1468-2632G>C		intron	N/A	ENSP00000396244.2
	MARVELD2	ENST00000413223.3	TSL:1	n.1156-2632G>C		intron	N/A	ENSP00000398922.2

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72358 AN: 151854 Hom.: 17402 Cov.: 31

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.467

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

GnomAD4 genome AF: 0.476 AC: 72388 AN: 151974 Hom.: 17400 Cov.: 31 AF XY: 0.484 AC XY: 35954 AN XY: 74280

African (AFR) AF: 0.409 AC: 16938 AN: 41442

American (AMR) AF: 0.523 AC: 7976 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1757 AN: 3466

East Asian (EAS) AF: 0.486 AC: 2508 AN: 5160

South Asian (SAS) AF: 0.535 AC: 2572 AN: 4810

European-Finnish (FIN) AF: 0.587 AC: 6194 AN: 10560

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32813 AN: 67958

Other (OTH) AF: 0.472 AC: 996 AN: 2112

Alfa AF: 0.477 Hom.: 2137

Bravo AF: 0.465

Asia WGS AF: 0.504 AC: 1753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.0
DANN	Benign	0.80
PhyloP100		0.44
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: rs2561182; hg19: chr5-68733645; COSMIC: COSV57780029;