rs104894365

chr12-25245345-C-Gchr12-25245345-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_004985.5(KRAS):c.40G>C(p.Val14Leu) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V14I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89

Genes affected

KRAS (HGNC:6407): (KRAS proto-oncogene, GTPase) This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_004985.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-25245345-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12589.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_033360.4	c.40G>C	p.Val14Leu	missense_variant	2/6	ENST00000256078.10
KRAS	NM_004985.5	c.40G>C	p.Val14Leu	missense_variant	2/5	ENST00000311936.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.40G>C	p.Val14Leu	missense_variant	2/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.40G>C	p.Val14Leu	missense_variant	2/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.2	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.96	D;.;D;.
Vest4		0.87
MutPred		0.76		Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.98

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: chr12-25398279;