5-69419483-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001038603.3(MARVELD2):c.98C>T(p.Thr33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,613,744 control chromosomes in the GnomAD database, including 192,292 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 17574 hom., cov: 31)

Exomes 𝑓: 0.49 ( 174718 hom. )

Consequence

MARVELD2
NM_001038603.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.537

Publications

43 publications found

Variant links:

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

MARVELD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.864055E-5).

BP6

Variant 5-69419483-C-T is Benign according to our data. Variant chr5-69419483-C-T is described in ClinVar as [Benign]. Clinvar id is 43847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARVELD2	NM_001038603.3 link	c.98C>T	p.Thr33Ile	missense_variant	Exon 2 of 7	ENST00000325631.10	NP_001033692.2	Q8N4S9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10 link	c.98C>T	p.Thr33Ile	missense_variant	Exon 2 of 7	1	NM_001038603.3	ENSP00000323264.5		Q8N4S9-1

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72719

AN:

151800

Hom.:

17577

Cov.:

show subpopulations

Gnomad AFR

AF:

0.415

Gnomad AMI

AF:

0.560

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.506

Gnomad EAS

AF:

0.494

Gnomad SAS

AF:

0.535

Gnomad FIN

AF:

0.585

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.483

Gnomad OTH

AF:

0.475

GnomAD2 exomes

AF:

0.501

AC:

125885

AN:

251326

AF XY:

0.502

show subpopulations

Gnomad AFR exome

AF:

0.417

Gnomad AMR exome

AF:

0.519

Gnomad ASJ exome

AF:

0.526

Gnomad EAS exome

AF:

0.477

Gnomad FIN exome

AF:

0.583

Gnomad NFE exome

AF:

0.483

Gnomad OTH exome

AF:

0.510

GnomAD4 exome

AF:

0.487

AC:

712553

AN:

1461828

Hom.:

174718

Cov.:

AF XY:

0.489

AC XY:

355752

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.423

AC:

14158

AN:

33478

American (AMR)

AF:

0.522

AC:

23338

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.528

AC:

13804

AN:

26136

East Asian (EAS)

AF:

0.521

AC:

20688

AN:

39700

South Asian (SAS)

AF:

0.538

AC:

46391

AN:

86256

European-Finnish (FIN)

AF:

0.579

AC:

30944

AN:

53418

Middle Eastern (MID)

AF:

0.505

AC:

2911

AN:

5768

European-Non Finnish (NFE)

AF:

0.477

AC:

530464

AN:

1111972

Other (OTH)

AF:

0.494

AC:

29855

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

24047

48094

72140

96187

120234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.479

AC:

72748

AN:

151916

Hom.:

17574

Cov.:

AF XY:

0.487

AC XY:

36141

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.415

AC:

17173

AN:

41424

American (AMR)

AF:

0.527

AC:

8033

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.506

AC:

1756

AN:

3470

East Asian (EAS)

AF:

0.493

AC:

2547

AN:

5162

South Asian (SAS)

AF:

0.535

AC:

2567

AN:

4802

European-Finnish (FIN)

AF:

0.585

AC:

6171

AN:

10542

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.483

AC:

32853

AN:

67956

Other (OTH)

AF:

0.480

AC:

1007

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1898

3797

5695

7594

9492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.481

Hom.:

81855

Bravo

AF:

0.469

TwinsUK

AF:

0.471

AC:

1746

ALSPAC

AF:

0.490

AC:

1887

ESP6500AA

AF:

0.424

AC:

1870

ESP6500EA

AF:

0.490

AC:

4210

ExAC

AF:

0.499

AC:

60647

Asia WGS

AF:

0.510

AC:

1772

AN:

3478

EpiCase

AF:

0.475

EpiControl

AF:

0.476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr33Ile in Exon 02 of MARVELD2: This variant is not expected to have clinical s ignificance because it has been identified in 48.6% (3413/7020) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs1185246). -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 49

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.1

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0083

.;T;T;T;.;T;T;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.57

.;.;.;T;T;T;T;T

MetaRNN

Benign

0.000089

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

L;L;L;L;L;.;.;.

PhyloP100

-0.54

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.71

.;N;.;.;N;N;N;N

REVEL

Benign

0.020

Sift

Benign

0.074

.;T;.;.;D;T;T;T

Sift4G

Benign

0.14

.;T;.;.;T;T;T;T

Polyphen

0.078

B;B;B;B;B;.;.;.

Vest4

0.16, 0.15, 0.038

MPC

0.080

ClinPred

0.0053

GERP RS

0.19

PromoterAI

0.0044

Neutral

(source)

Varity_R

0.028

gMVP

0.096

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

5-69419483-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over