12-25245321-G-C

Variant names:

• chr12-25245321-G-C
• rs121913236
• NM_004985.5:c.64C>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_004985.5(KRAS):​c.64C>G​(p.Gln22Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q22R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.98

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 5 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 chr12-25245320-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 40452.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 12-25245321-G-C is Pathogenic according to our data. Variant chr12-25245321-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40451.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.64C>G	p.Gln22Glu	missense_variant	Exon 2 of 5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.64C>G	p.Gln22Glu	missense_variant	Exon 2 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460514 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726428

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Pathogenic:1

Jun 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to be de novo with confirmed paternity in an individual affected with Noonan syndrome (PMID: 17056636) and has also been reported in an individual with cardio-facial-cutaneous syndrome or possibly Noonan syndrome (PMID: 17324647). Experimental studies have shown that this missense change disrupts the normal function of KRAS (PMID: 24803665, 20949621). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamine with glutamic acid at codon 22 of the KRAS protein (p.Gln22Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	.;.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.6	H;.;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	N;D;N;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.69	P;.;D;.
Vest4		0.93
MutPred		0.82		Gain of catalytic residue at S17 (P = 0.0017);Gain of catalytic residue at S17 (P = 0.0017);Gain of catalytic residue at S17 (P = 0.0017);Gain of catalytic residue at S17 (P = 0.0017);
MVP		0.98
MPC		2.6
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.97
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs121913236; hg19: chr12-25398255;