13-38688532-G-C

Variant names:

• chr13-38688532-G-C
• rs61997174
• NM_207361.6:c.1188G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.89

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]

ACMG classification

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 rank	MANE	Protein	UniProt
FREM2	NM_207361.6	c.1188G>C	p.Gln396His	missense_variant	Exon 1 of 24	ENST00000280481.9	NP_997244.4
FREM2	XM_017020554.2	c.1188G>C	p.Gln396His	missense_variant	Exon 1 of 3		XP_016876043.1
FREM2	XR_941571.3	n.1456G>C		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	c.1188G>C	p.Gln396His	missense_variant	Exon 1 of 24	1	NM_207361.6	ENSP00000280481.7

Frequencies

GnomAD3 genomes AF: 0.00688 AC: 1046 AN: 152078 Hom.: 20 Cov.: 32

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.: 9 AF XY: 0.00137 AC XY: 186 AN XY: 135722

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.: 11 Cov.: 46 AF XY: 0.000553 AC XY: 402 AN XY: 727136

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.: 20 Cov.: 32 AF XY: 0.00636 AC XY: 473 AN XY: 74418

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.: 0

Bravo AF: 0.00800

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00245 AC: 298

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 26, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.18
Sift	Benign	0.040	D
Sift4G	Uncertain	0.018	D
Vest4		0.54
MutPred		0.49		Gain of sheet (P = 0.0149);
MVP		0.65
MPC		0.14
ClinPred		0.055	T
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

Other links and lift over

dbSNP: rs61997174; hg19: chr13-39262669;