chr12-25245350-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong
The NM_033360.4(KRAS):c.35G>A(p.Gly12Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,744 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12F) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
KRAS
NM_033360.4 missense
NM_033360.4 missense
Scores
10
7
1
Clinical Significance
Conservation
PhyloP100: 7.89
Publications
13246 publications found
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 2Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- cardiofaciocutaneous syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
- linear nevus sebaceous syndromeInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Costello syndromeInheritance: 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 15 ACMG points.
PM1
In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_033360.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-25245350-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 45122.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: 2.7433 (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, 0.898
PP5
Variant 12-25245350-C-T is Pathogenic according to our data. Variant chr12-25245350-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_033360.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KRAS | NM_033360.4 | MANE Plus Clinical | c.35G>A | p.Gly12Asp | missense | Exon 2 of 6 | NP_203524.1 | ||
| KRAS | NM_004985.5 | MANE Select | c.35G>A | p.Gly12Asp | missense | Exon 2 of 5 | NP_004976.2 | ||
| KRAS | NM_001369786.1 | c.35G>A | p.Gly12Asp | missense | Exon 2 of 6 | NP_001356715.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KRAS | ENST00000256078.10 | TSL:1 MANE Plus Clinical | c.35G>A | p.Gly12Asp | missense | Exon 2 of 6 | ENSP00000256078.5 | ||
| KRAS | ENST00000311936.8 | TSL:1 MANE Select | c.35G>A | p.Gly12Asp | missense | Exon 2 of 5 | ENSP00000308495.3 | ||
| KRAS | ENST00000556131.2 | TSL:1 | c.35G>A | p.Gly12Asp | missense | Exon 2 of 3 | ENSP00000451856.1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152182
Hom.:
Cov.:
32
Gnomad AFR
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Gnomad AMR
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Gnomad ASJ
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Gnomad EAS
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Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD2 exomes AF: 0.00000401 AC: 1AN: 249328 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
249328
AF XY:
Gnomad AFR exome
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Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460562Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726500 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
4
AN:
1460562
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
726500
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33466
American (AMR)
AF:
AC:
0
AN:
44652
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26054
East Asian (EAS)
AF:
AC:
0
AN:
39666
South Asian (SAS)
AF:
AC:
0
AN:
85970
European-Finnish (FIN)
AF:
AC:
0
AN:
53374
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
3
AN:
1111282
Other (OTH)
AF:
AC:
1
AN:
60330
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000148366), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.350
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
2
AN:
152182
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74354
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41438
American (AMR)
AF:
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5202
South Asian (SAS)
AF:
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
2
AN:
68024
Other (OTH)
AF:
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ExAC
AF:
AC:
2
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts