13-38687430-GGCTGCTGCT-GGCTGCTGCTGCTGCTGCT

Variant names:

• chr13-38687430-G-GGCTGCTGCT
• rs568736669
• NM_207361.6:c.99_107dupGCTGCTGCT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_207361.6(FREM2):​c.99_107dupGCTGCTGCT​(p.Leu34_Leu36dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FREM2 NM_207361.6 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM2	NM_207361.6	c.99_107dupGCTGCTGCT	p.Leu34_Leu36dup	disruptive_inframe_insertion	Exon 1 of 24	ENST00000280481.9	NP_997244.4
FREM2	XM_017020554.2	c.99_107dupGCTGCTGCT	p.Leu34_Leu36dup	disruptive_inframe_insertion	Exon 1 of 3		XP_016876043.1
FREM2	XR_941571.3	n.367_375dupGCTGCTGCT		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.99_107dupGCTGCTGCT	p.Leu34_Leu36dup	disruptive_inframe_insertion	Exon 1 of 24	1	NM_207361.6	ENSP00000280481.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447036 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 718638

African (AFR) AF: 0.00 AC: 0 AN: 33172

American (AMR) AF: 0.00 AC: 0 AN: 42896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25782

East Asian (EAS) AF: 0.00 AC: 0 AN: 39026

South Asian (SAS) AF: 0.00 AC: 0 AN: 84192

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 50944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105516

Other (OTH) AF: 0.00 AC: 0 AN: 59776

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.24

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs568736669; hg19: chr13-39261567;