13-38856177-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_207361.6(FREM2):c.6977C>T(p.Thr2326Ile) variant causes a missense change. The variant allele was found at a frequency of 0.717 in 1,610,012 control chromosomes in the GnomAD database, including 416,843 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 41391 hom., cov: 31)

Exomes 𝑓: 0.71 ( 375452 hom. )

Consequence

FREM2
NM_207361.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.12

Publications

33 publications found

Variant links:

Genes affected

FREM2 (HGNC:25396): (FRAS1 related extracellular matrix 2) This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The encoded protein localizes to the basement membrane, forming a ternary complex that plays a role in epidermal-dermal interactions. This protein is important for the integrity of skin and renal epithelia. Mutations in this gene are associated with Fraser syndrome. [provided by RefSeq, Apr 2014]

FREM2 Gene-Disease associations (from GenCC):

Fraser syndrome 2
Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
Fraser syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fraser syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FREM2 links:

ENSG00000294617 (HGNC:):

ENSG00000294617 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=7.068395E-7).

BP6

Variant 13-38856177-C-T is Benign according to our data. Variant chr13-38856177-C-T is described in ClinVar as Benign. ClinVar VariationId is 263300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM2	NM_207361.6 link	c.6977C>T	p.Thr2326Ile	missense_variant	Exon 12 of 24	ENST00000280481.9	NP_997244.4	Q5SZK8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9 link	c.6977C>T	p.Thr2326Ile	missense_variant	Exon 12 of 24	1	NM_207361.6	ENSP00000280481.7		Q5SZK8-1
ENSG00000294617	ENST00000724728.1 link	n.135-4244G>A		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.735

AC:

111649

AN:

151862

Hom.:

41344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.753

Gnomad AMI

AF:

0.759

Gnomad AMR

AF:

0.775

Gnomad ASJ

AF:

0.725

Gnomad EAS

AF:

0.968

Gnomad SAS

AF:

0.721

Gnomad FIN

AF:

0.742

Gnomad MID

AF:

0.705

Gnomad NFE

AF:

0.699

Gnomad OTH

AF:

0.730

GnomAD2 exomes

AF:

0.749

AC:

188242

AN:

251354

AF XY:

0.741

show subpopulations

Gnomad AFR exome

AF:

0.750

Gnomad AMR exome

AF:

0.836

Gnomad ASJ exome

AF:

0.728

Gnomad EAS exome

AF:

0.971

Gnomad FIN exome

AF:

0.746

Gnomad NFE exome

AF:

0.698

Gnomad OTH exome

AF:

0.728

GnomAD4 exome

AF:

0.715

AC:

1042168

AN:

1458032

Hom.:

375452

Cov.:

AF XY:

0.715

AC XY:

518764

AN XY:

725570

show subpopulations

African (AFR)

AF:

0.752

AC:

25115

AN:

33404

American (AMR)

AF:

0.830

AC:

37107

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.726

AC:

18952

AN:

26090

East Asian (EAS)

AF:

0.972

AC:

38538

AN:

39648

South Asian (SAS)

AF:

0.715

AC:

61656

AN:

86186

European-Finnish (FIN)

AF:

0.748

AC:

39891

AN:

53364

Middle Eastern (MID)

AF:

0.703

AC:

4045

AN:

5758

European-Non Finnish (NFE)

AF:

0.698

AC:

773333

AN:

1108658

Other (OTH)

AF:

0.723

AC:

43531

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

13275

26550

39826

53101

66376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19664

39328

58992

78656

98320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.735

AC:

111754

AN:

151980

Hom.:

41391

Cov.:

AF XY:

0.737

AC XY:

54733

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.753

AC:

31192

AN:

41430

American (AMR)

AF:

0.775

AC:

11831

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.725

AC:

2517

AN:

3470

East Asian (EAS)

AF:

0.967

AC:

4990

AN:

5160

South Asian (SAS)

AF:

0.723

AC:

3489

AN:

4828

European-Finnish (FIN)

AF:

0.742

AC:

7832

AN:

10562

Middle Eastern (MID)

AF:

0.700

AC:

203

AN:

290

European-Non Finnish (NFE)

AF:

0.699

AC:

47469

AN:

67958

Other (OTH)

AF:

0.729

AC:

1540

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1478

2955

4433

5910

7388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

846

1692

2538

3384

4230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.718

Hom.:

117764

Bravo

AF:

0.742

TwinsUK

AF:

0.693

AC:

2569

ALSPAC

AF:

0.714

AC:

2751

ESP6500AA

AF:

0.764

AC:

3365

ESP6500EA

AF:

0.700

AC:

6024

ExAC

AF:

0.740

AC:

89796

Asia WGS

AF:

0.817

AC:

2844

AN:

3478

EpiCase

AF:

0.695

EpiControl

AF:

0.695

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Fraser syndrome 1

Benign:3

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fraser syndrome 2

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Isolated cryptophthalmia

Benign:1

Aug 10, 2021

Genome-Nilou Lab

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

0.044

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.017

MetaRNN

Benign

7.1e-7

MetaSVM

Benign

-0.96

PhyloP100

6.1

PrimateAI

Benign

0.43

PROVEAN

Benign

2.3

REVEL

Benign

0.13

Sift

Benign

0.26

Sift4G

Benign

0.080

Vest4

0.044

MPC

0.13

ClinPred

0.016

GERP RS

5.7

gMVP

0.083

Mutation Taster

=96/4

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

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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