FREM2 p.Gln396His

Variant names:

• chr13-38688532-G-T
• NM_207361.6:c.1188G>T
• FREM2 p.Gln396His

Your query was ambiguous. Multiple possible variants found:

• chr13-38688532-G-T
• chr13-38688532-G-C

Variant summary

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

The NM_207361.6(FREM2):​c.1188G>T​(p.Gln396His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q396Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FREM2 NM_207361.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.89
• 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: 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

ACMG classification

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

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

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.1188G>T	p.Gln396His	missense	Exon 1 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.1188G>T	p.Gln396His	missense	Exon 1 of 24	ENSP00000280481.7	Q5SZK8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.17	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
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.9
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.19
Sift	Benign	0.040	D
Sift4G	Uncertain	0.018	D
gMVP		0.75
Mutation Taster		=90/10	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr13-39262669;