NM_207361.6:c.6977C>T

Variant names:

• chr13-38856177-C-T
• rs9548509
• NM_207361.6:c.6977C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207361.6(FREM2):​c.6977C>T​(p.Thr2326Ile) variant causes a missense change. The variant allele was found at a frequency of 0.717 in 1,610,012 control chromosomes in the GnomAD database, including 416,843 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41391 hom., cov: 31)
  • Exomes 𝑓: 0.71 (375452 hom.)
• Consequence: FREM2 NM_207361.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.12
• Publications: 33 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

ENSG00000294617 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.068395E-7).
• BP6: Variant 13-38856177-C-T is Benign according to our data. Variant chr13-38856177-C-T is described in ClinVar as Benign. ClinVar VariationId is 263300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 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.6977C>T	p.Thr2326Ile	missense	Exon 12 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.6977C>T	p.Thr2326Ile	missense	Exon 12 of 24	ENSP00000280481.7	Q5SZK8-1
	ENSG00000294617	ENST00000724728.1		n.135-4244G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111649 AN: 151862 Hom.: 41344 Cov.: 31

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.725

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.705

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.730

GnomAD2 exomes AF: 0.749 AC: 188242 AN: 251354 AF XY: 0.741

Gnomad AFR exome AF: 0.750

Gnomad AMR exome AF: 0.836

Gnomad ASJ exome AF: 0.728

Gnomad EAS exome AF: 0.971

Gnomad FIN exome AF: 0.746

Gnomad NFE exome AF: 0.698

Gnomad OTH exome AF: 0.728

GnomAD4 exome AF: 0.715 AC: 1042168 AN: 1458032 Hom.: 375452 Cov.: 32 AF XY: 0.715 AC XY: 518764 AN XY: 725570

African (AFR) AF: 0.752 AC: 25115 AN: 33404

American (AMR) AF: 0.830 AC: 37107 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 18952 AN: 26090

East Asian (EAS) AF: 0.972 AC: 38538 AN: 39648

South Asian (SAS) AF: 0.715 AC: 61656 AN: 86186

European-Finnish (FIN) AF: 0.748 AC: 39891 AN: 53364

Middle Eastern (MID) AF: 0.703 AC: 4045 AN: 5758

European-Non Finnish (NFE) AF: 0.698 AC: 773333 AN: 1108658

Other (OTH) AF: 0.723 AC: 43531 AN: 60226

GnomAD4 genome AF: 0.735 AC: 111754 AN: 151980 Hom.: 41391 Cov.: 31 AF XY: 0.737 AC XY: 54733 AN XY: 74278

African (AFR) AF: 0.753 AC: 31192 AN: 41430

American (AMR) AF: 0.775 AC: 11831 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 2517 AN: 3470

East Asian (EAS) AF: 0.967 AC: 4990 AN: 5160

South Asian (SAS) AF: 0.723 AC: 3489 AN: 4828

European-Finnish (FIN) AF: 0.742 AC: 7832 AN: 10562

Middle Eastern (MID) AF: 0.700 AC: 203 AN: 290

European-Non Finnish (NFE) AF: 0.699 AC: 47469 AN: 67958

Other (OTH) AF: 0.729 AC: 1540 AN: 2112

Alfa AF: 0.718 Hom.: 117764

Bravo AF: 0.742

TwinsUK AF: 0.693 AC: 2569

ALSPAC AF: 0.714 AC: 2751

ESP6500AA AF: 0.764 AC: 3365

ESP6500EA AF: 0.700 AC: 6024

ExAC AF: 0.740 AC: 89796

Asia WGS AF: 0.817 AC: 2844 AN: 3478

EpiCase AF: 0.695

EpiControl AF: 0.695

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fraser syndrome 1 (3)
-	-	3	not provided (3)
-	-	2	Fraser syndrome 2 (2)
-	-	1	Isolated cryptophthalmia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.96
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.017	N
MetaRNN	Benign	7.1e-7	T
MetaSVM	Benign	-0.96	T
PhyloP100		6.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.13
Sift	Benign	0.26	T
Sift4G	Benign	0.080	T
Vest4		0.044
MPC		0.13
ClinPred		0.016	T
GERP RS		5.7
gMVP		0.083
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9548509; hg19: chr13-39430314; COSMIC: COSV54846526;