12-69574164-C-A

Variant names:

• chr12-69574164-C-A
• NM_001278356.2:c.736C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278356.2(FRS2):​c.736C>A​(p.Pro246Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FRS2 NM_001278356.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25792933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRS2	NM_001278356.2	c.736C>A	p.Pro246Thr	missense_variant	Exon 9 of 9	ENST00000549921.6	NP_001265285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRS2	ENST00000549921.6	c.736C>A	p.Pro246Thr	missense_variant	Exon 9 of 9	1	NM_001278356.2	ENSP00000450048.1
FRS2	ENST00000550389.5	c.736C>A	p.Pro246Thr	missense_variant	Exon 7 of 7	1		ENSP00000447241.1
FRS2	ENST00000397997.6	c.736C>A	p.Pro246Thr	missense_variant	Exon 7 of 7	5		ENSP00000381083.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.736C>A (p.P246T) alteration is located in exon 10 (coding exon 5) of the FRS2 gene. This alteration results from a C to A substitution at nucleotide position 736, causing the proline (P) at amino acid position 246 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.72	D;D;D
Eigen	Benign	-0.13
Eigen_PC	Benign	0.0024
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;.;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.29	B;B;B
Vest4		0.66
MutPred		0.40		Gain of catalytic residue at E247 (P = 0.0069);Gain of catalytic residue at E247 (P = 0.0069);Gain of catalytic residue at E247 (P = 0.0069);
MVP		0.53
ClinPred		0.69	D
GERP RS		4.1
Varity_R		0.23
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-69967944;