13-38689594-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_207361.6(FREM2):c.2250C>T(p.Asp750Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,612,632 control chromosomes in the GnomAD database, including 10,162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 644 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9518 hom. )

Consequence

FREM2
NM_207361.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.177

Publications

16 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 13-38689594-C-T is Benign according to our data. Variant chr13-38689594-C-T is described in ClinVar as Benign. ClinVar VariationId is 193537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.177 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM2	NM_207361.6 link	c.2250C>T	p.Asp750Asp	synonymous_variant	Exon 1 of 24	ENST00000280481.9	NP_997244.4	Q5SZK8-1
FREM2	XM_017020554.2 link	c.2250C>T	p.Asp750Asp	synonymous_variant	Exon 1 of 3		XP_016876043.1
FREM2	XR_941571.3 link	n.2518C>T		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9 link	c.2250C>T	p.Asp750Asp	synonymous_variant	Exon 1 of 24	1	NM_207361.6	ENSP00000280481.7		Q5SZK8-1

Frequencies

GnomAD3 genomes

AF:

0.0823

AC:

12512

AN:

152016

Hom.:

643

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.0855

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.0817

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.0946

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0937

GnomAD2 exomes

AF:

0.105

AC:

26361

AN:

250408

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0182

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.0732

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.0923

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.109

AC:

159806

AN:

1460498

Hom.:

9518

Cov.:

AF XY:

0.112

AC XY:

81215

AN XY:

726382

show subpopulations

African (AFR)

AF:

0.0170

AC:

568

AN:

33466

American (AMR)

AF:

0.105

AC:

4665

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.0768

AC:

1999

AN:

26022

East Asian (EAS)

AF:

0.130

AC:

5149

AN:

39678

South Asian (SAS)

AF:

0.185

AC:

15887

AN:

86078

European-Finnish (FIN)

AF:

0.0920

AC:

4913

AN:

53374

Middle Eastern (MID)

AF:

0.0838

AC:

483

AN:

5762

European-Non Finnish (NFE)

AF:

0.108

AC:

119861

AN:

1111164

Other (OTH)

AF:

0.104

AC:

6281

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

7674

15347

23021

30694

38368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4504

9008

13512

18016

22520

<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:

0.0822

AC:

12512

AN:

152134

Hom.:

644

Cov.:

AF XY:

0.0836

AC XY:

6213

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0194

AC:

806

AN:

41524

American (AMR)

AF:

0.103

AC:

1568

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0817

AC:

283

AN:

3466

East Asian (EAS)

AF:

0.102

AC:

528

AN:

5162

South Asian (SAS)

AF:

0.193

AC:

929

AN:

4806

European-Finnish (FIN)

AF:

0.0946

AC:

1001

AN:

10582

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7097

AN:

67982

Other (OTH)

AF:

0.0941

AC:

199

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

578

1155

1733

2310

2888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0719

Hom.:

417

Bravo

AF:

0.0787

Asia WGS

AF:

0.143

AC:

499

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.108

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

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:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fraser syndrome 2

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.4

(source)

DANN

Benign

0.66

PhyloP100

0.18

Mutation Taster

=100/0

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