13-38688532-G-C

Position:

chr13-38688532-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_207361.6(FREM2):c.1188G>C(p.Gln396His) variant causes a missense change. The variant allele was found at a frequency of 0.00123 in 1,613,890 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 20 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 11 hom. )

Consequence

FREM2
NM_207361.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.89

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 links:

FREM2 (HGNC:):

FREM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009462327).

BP6

Variant 13-38688532-G-C is Benign according to our data. Variant chr13-38688532-G-C is described in ClinVar as [Benign]. Clinvar id is 235731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-38688532-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0069 (1050/152194) while in subpopulation AFR AF= 0.0242 (1007/41530). AF 95% confidence interval is 0.023. There are 20 homozygotes in gnomad4. There are 473 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM2	NM_207361.6 linkuse as main transcript	c.1188G>C	p.Gln396His	missense_variant	1/24	ENST00000280481.9	NP_997244.4	Q5SZK8-1
FREM2	XM_017020554.2 linkuse as main transcript	c.1188G>C	p.Gln396His	missense_variant	1/3		XP_016876043.1
FREM2	XR_941571.3 linkuse as main transcript	n.1456G>C		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9 linkuse as main transcript	c.1188G>C	p.Gln396His	missense_variant	1/24	1	NM_207361.6	ENSP00000280481.7		Q5SZK8-1

Frequencies

GnomAD3 genomes

AF:

0.00688

AC:

1046

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00178

AC:

447

AN:

251060

Hom.:

AF XY:

0.00137

AC XY:

186

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.0247

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000636

AC:

929

AN:

1461696

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

402

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0234

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00690

AC:

1050

AN:

152194

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

473

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0242

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.00800

ESP6500AA

AF:

0.0286

AC:

126

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00245

AC:

298

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2015	- -

Fraser syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

MetaRNN

Benign

0.0095

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.18

Sift

Benign

0.040

Sift4G

Uncertain

0.018

Vest4

0.54

MutPred

0.49

Gain of sheet (P = 0.0149);

MVP

0.65

MPC

0.14

ClinPred

0.055

GERP RS

5.9

gMVP

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over