Genetic Variant KRAS:c.451-2968G>A (chr12-25218528-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033360.4(KRAS):c.451-2968G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 151,710 control chromosomes in the GnomAD database, including 4,463 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 4463 hom., cov: 31)

Consequence

KRAS
NM_033360.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0500

Publications

13 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

KRAS links:

LOC124902899 (HGNC:):

LOC124902899 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KRAS	NM_033360.4	MANE Plus Clinical	c.451-2968G>A	intron	N/A	NP_203524.1
KRAS	NM_004985.5	MANE Select	c.450+7086G>A	intron	N/A	NP_004976.2
KRAS	NM_001369786.1		c.451-2968G>A	intron	N/A	NP_001356715.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.451-2968G>A	intron	N/A	ENSP00000256078.5
KRAS	ENST00000311936.8	TSL:1 MANE Select	c.450+7086G>A	intron	N/A	ENSP00000308495.3
KRAS	ENST00000685328.1		c.450+7086G>A	intron	N/A	ENSP00000508921.1

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36301

AN:

151590

Hom.:

4455

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.278

Gnomad ASJ

AF:

0.183

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.207

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.236

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.239

AC:

36329

AN:

151710

Hom.:

4463

Cov.:

AF XY:

0.240

AC XY:

17790

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.247

AC:

10203

AN:

41334

American (AMR)

AF:

0.278

AC:

4240

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

636

AN:

3466

East Asian (EAS)

AF:

0.102

AC:

527

AN:

5158

South Asian (SAS)

AF:

0.137

AC:

654

AN:

4786

European-Finnish (FIN)

AF:

0.306

AC:

3211

AN:

10508

Middle Eastern (MID)

AF:

0.199

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.237

AC:

16121

AN:

67886

Other (OTH)

AF:

0.233

AC:

492

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1392

2784

4175

5567

6959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.218

Hom.:

1672

Bravo

AF:

0.241

Asia WGS

AF:

0.105

AC:

363

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.4

(source)

DANN

Benign

0.55

PhyloP100

-0.050

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over