dbSNP rs9532292: FREM2:p.Thr2466Thr (chr13-38859469-A-G) – ACMG Classification: Benign (-21 pts)

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.7398A>G(p.Thr2466Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,613,642 control chromosomes in the GnomAD database, including 98,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12582 hom., cov: 31)

Exomes 𝑓: 0.34 ( 86100 hom. )

Consequence

FREM2
NM_207361.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -6.37

Publications

22 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: Ambry Genetics, G2P
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 13-38859469-A-G is Benign according to our data. Variant chr13-38859469-A-G is described in ClinVar as Benign. ClinVar VariationId is 263301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.36 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207361.6. 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
	FREM2	NM_207361.6	MANE Select	c.7398A>G	p.Thr2466Thr	synonymous	Exon 14 of 24	NP_997244.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM2	ENST00000280481.9	TSL:1 MANE Select	c.7398A>G	p.Thr2466Thr	synonymous	Exon 14 of 24	ENSP00000280481.7	Q5SZK8-1
	ENSG00000294617	ENST00000724728.1		n.134+2433T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.391

AC:

59255

AN:

151738

Hom.:

12538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.552

Gnomad AMI

AF:

0.312

Gnomad AMR

AF:

0.386

Gnomad ASJ

AF:

0.409

Gnomad EAS

AF:

0.384

Gnomad SAS

AF:

0.447

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.313

Gnomad OTH

AF:

0.364

GnomAD2 exomes

AF:

0.373

AC:

93785

AN:

251218

AF XY:

0.368

show subpopulations

Gnomad AFR exome

AF:

0.560

Gnomad AMR exome

AF:

0.473

Gnomad ASJ exome

AF:

0.410

Gnomad EAS exome

AF:

0.383

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.313

Gnomad OTH exome

AF:

0.348

GnomAD4 exome

AF:

0.337

AC:

493132

AN:

1461786

Hom.:

86100

Cov.:

AF XY:

0.340

AC XY:

246915

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.559

AC:

18727

AN:

33476

American (AMR)

AF:

0.469

AC:

20963

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.403

AC:

10531

AN:

26136

East Asian (EAS)

AF:

0.386

AC:

15306

AN:

39686

South Asian (SAS)

AF:

0.447

AC:

38574

AN:

86258

European-Finnish (FIN)

AF:

0.259

AC:

13843

AN:

53420

Middle Eastern (MID)

AF:

0.404

AC:

2332

AN:

5766

European-Non Finnish (NFE)

AF:

0.316

AC:

351663

AN:

1111928

Other (OTH)

AF:

0.351

AC:

21193

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

19720

39441

59161

78882

98602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11808

23616

35424

47232

59040

<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:

0.391

AC:

59353

AN:

151856

Hom.:

12582

Cov.:

AF XY:

0.389

AC XY:

28879

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.552

AC:

22846

AN:

41378

American (AMR)

AF:

0.387

AC:

5912

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.409

AC:

1417

AN:

3468

East Asian (EAS)

AF:

0.385

AC:

1973

AN:

5128

South Asian (SAS)

AF:

0.450

AC:

2163

AN:

4812

European-Finnish (FIN)

AF:

0.248

AC:

2616

AN:

10566

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.313

AC:

21272

AN:

67928

Other (OTH)

AF:

0.359

AC:

755

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1722

3444

5166

6888

8610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.342

Hom.:

38077

Bravo

AF:

0.412

Asia WGS

AF:

0.412

AC:

1438

AN:

3478

EpiCase

AF:

0.319

EpiControl

AF:

0.317

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fraser syndrome 2 (2)

not provided (2)

Isolated cryptophthalmia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.090

(source)

DANN

Benign

0.47

PhyloP100

-6.4

Mutation Taster

=95/5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over