chr12-117469747-A-G

Position:

• chr12-117469747-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173598.6(KSR2):​c.2761T>C​(p.Phe921Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KSR2 NM_173598.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.26

Genes affected

KSR2 (HGNC:18610): (kinase suppressor of ras 2) Predicted to enable MAP-kinase scaffold activity; mitogen-activated protein kinase kinase binding activity; and protein kinase activity. Predicted to be involved in Ras protein signal transduction; calcium-mediated signaling; and positive regulation of cold-induced thermogenesis. Predicted to act upstream of or within positive regulation of MAPK cascade. Predicted to be active in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KSR2	NM_173598.6	c.2761T>C	p.Phe921Leu	missense_variant	19/20	ENST00000339824.7	NP_775869.4
KSR2	XM_011538224.4	c.2755T>C	p.Phe919Leu	missense_variant	19/20		XP_011536526.1
KSR2	XM_011538225.4	c.2398T>C	p.Phe800Leu	missense_variant	19/20		XP_011536527.1
KSR2	XM_017019210.3	c.1456T>C	p.Phe486Leu	missense_variant	14/15		XP_016874699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KSR2	ENST00000339824.7	c.2761T>C	p.Phe921Leu	missense_variant	19/20	5	NM_173598.6	ENSP00000339952.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2024

The c.2674T>C (p.F892L) alteration is located in exon 19 (coding exon 19) of the KSR2 gene. This alteration results from a T to C substitution at nucleotide position 2674, causing the phenylalanine (F) at amino acid position 892 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.66		.;Gain of ubiquitination at K923 (P = 0.0913);
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.91
gMVP		0.69

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-117907552;