chr12-69574420-C-T

Variant names:

• chr12-69574420-C-T
• NM_001278356.2:c.992C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278356.2(FRS2):​c.992C>T​(p.Ser331Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRS2 NM_001278356.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08
• Publications: 0 publications found

Genes affected

FRS2 (HGNC:16971): (fibroblast growth factor receptor substrate 2) Enables fibroblast growth factor receptor binding activity and neurotrophin TRKA receptor binding activity. Involved in negative regulation of cardiac muscle cell differentiation. Acts upstream of or within fibroblast growth factor receptor signaling pathway. Located in adherens junction. Biomarker of renal cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21601117).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278356.2. 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
	FRS2	NM_001278356.2	MANE Select	c.992C>T	p.Ser331Leu	missense	Exon 9 of 9	NP_001265285.1	Q8WU20
	FRS2	NM_001042555.3		c.992C>T	p.Ser331Leu	missense	Exon 10 of 10	NP_001036020.1	L7RTG7
	FRS2	NM_001278351.2		c.992C>T	p.Ser331Leu	missense	Exon 11 of 11	NP_001265280.1	L7RTG7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRS2	ENST00000549921.6	TSL:1 MANE Select	c.992C>T	p.Ser331Leu	missense	Exon 9 of 9	ENSP00000450048.1	Q8WU20
	FRS2	ENST00000550389.5	TSL:1	c.992C>T	p.Ser331Leu	missense	Exon 7 of 7	ENSP00000447241.1	Q8WU20
	FRS2	ENST00000397997.6	TSL:5	c.992C>T	p.Ser331Leu	missense	Exon 7 of 7	ENSP00000381083.2	Q8WU20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		7.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Benign	0.065	T
Sift4G	Benign	0.18	T
Polyphen		0.16	B
Vest4		0.33
MutPred		0.26		Gain of catalytic residue at S327 (P = 0.0202)
MVP		0.72
ClinPred		0.82	D
GERP RS		6.0
Varity_R		0.13
gMVP		0.30
Mutation Taster		=92/8	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

Other links and lift over

hg19: chr12-69968200;