rs299093

Variant names:

• chr5-69422112-A-G
• rs299093
• NM_001038603.3:c.1146+1581A>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.1146+1581A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 151,810 control chromosomes in the GnomAD database, including 17,575 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 (17575 hom., cov: 31)
• Consequence: MARVELD2 NM_001038603.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.518 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	NM_001038603.3	MANE Select	c.1146+1581A>G		intron	N/A	NP_001033692.2	Q8N4S9-1
	MARVELD2	NM_001244734.2		c.1146+1581A>G		intron	N/A	NP_001231663.1	Q8N4S9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	ENST00000325631.10	TSL:1 MANE Select	c.1146+1581A>G		intron	N/A	ENSP00000323264.5	Q8N4S9-1
	MARVELD2	ENST00000454295.6	TSL:1	c.1146+1581A>G		intron	N/A	ENSP00000396244.2	Q8N4S9-3
	MARVELD2	ENST00000413223.3	TSL:1	n.798+1581A>G		intron	N/A	ENSP00000398922.2	A1BQX2

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72736 AN: 151692 Hom.: 17577 Cov.: 31

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.475

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

GnomAD4 genome AF: 0.479 AC: 72767 AN: 151810 Hom.: 17575 Cov.: 31 AF XY: 0.487 AC XY: 36121 AN XY: 74150

African (AFR) AF: 0.416 AC: 17210 AN: 41382

American (AMR) AF: 0.527 AC: 8023 AN: 15228

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

East Asian (EAS) AF: 0.493 AC: 2542 AN: 5158

South Asian (SAS) AF: 0.535 AC: 2577 AN: 4816

European-Finnish (FIN) AF: 0.585 AC: 6137 AN: 10490

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

European-Non Finnish (NFE) AF: 0.484 AC: 32869 AN: 67956

Other (OTH) AF: 0.479 AC: 1009 AN: 2106

Alfa AF: 0.485 Hom.: 2360

Bravo AF: 0.470

Asia WGS AF: 0.510 AC: 1773 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.6
DANN	Benign	0.47
PhyloP100		0.16
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: rs299093; hg19: chr5-68717939; COSMIC: COSV57779916; COSMIC: COSV57779916;