NM_004985.5:c.211T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5

The NM_004985.5(KRAS):​c.211T>C​(p.Tyr71His) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y71D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KRAS
NM_004985.5 missense

Scores

11
6
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.31

Publications

26 publications found
Variant links:
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]
KRAS Gene-Disease associations (from GenCC):
  • cardiofaciocutaneous syndrome 2
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
  • Noonan syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • Noonan syndrome 3
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • cardiofaciocutaneous syndrome
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • linear nevus sebaceous syndrome
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Costello syndrome
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr12-25227313-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 228267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 65 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.3177 (below the threshold of 3.09). Trascript score misZ: 3.0857 (below the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Noonan syndrome, Costello syndrome, linear nevus sebaceous syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.884
PP5
Variant 12-25227313-A-G is Pathogenic according to our data. Variant chr12-25227313-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31940.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRASNM_004985.5 linkc.211T>C p.Tyr71His missense_variant Exon 3 of 5 ENST00000311936.8 NP_004976.2 P01116-2A0A024RAV5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRASENST00000311936.8 linkc.211T>C p.Tyr71His missense_variant Exon 3 of 5 1 NM_004985.5 ENSP00000308495.3 P01116-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Cardiofaciocutaneous syndrome 2 Pathogenic:1
Jan 15, 2013
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
.;D
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Uncertain
0.097
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Uncertain
2.5
M;M
PhyloP100
9.3
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.023
D;D
Sift4G
Benign
0.062
T;T
Polyphen
0.43
B;P
Vest4
0.95
MutPred
0.69
Gain of catalytic residue at T74 (P = 0.0026);Gain of catalytic residue at T74 (P = 0.0026);
MVP
0.97
MPC
3.0
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.93
gMVP
0.91
Mutation Taster
=2/98
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907205; hg19: chr12-25380247; API