chr12-25216683-A-G

Variant names:

• chr12-25216683-A-G
• rs12822857
• NM_033360.4:c.451-1123T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033360.4(KRAS):​c.451-1123T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 151,994 control chromosomes in the GnomAD database, including 19,385 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 0.49 (19385 hom., cov: 32)
• Consequence: KRAS NM_033360.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• Publications: 8 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 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

LOC124902899 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.779 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.451-1123T>C		intron	N/A	NP_203524.1
	KRAS	NM_004985.5	MANE Select	c.451-6772T>C		intron	N/A	NP_004976.2
	KRAS	NM_001369786.1		c.451-1123T>C		intron	N/A	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.451-1123T>C		intron	N/A	ENSP00000256078.5
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.451-6772T>C		intron	N/A	ENSP00000308495.3
	KRAS	ENST00000685328.1		c.451-6772T>C		intron	N/A	ENSP00000508921.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74832 AN: 151876 Hom.: 19373 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.506

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

GnomAD4 genome AF: 0.493 AC: 74874 AN: 151994 Hom.: 19385 Cov.: 32 AF XY: 0.498 AC XY: 37002 AN XY: 74278

African (AFR) AF: 0.328 AC: 13612 AN: 41462

American (AMR) AF: 0.501 AC: 7653 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2163 AN: 3468

East Asian (EAS) AF: 0.800 AC: 4130 AN: 5164

South Asian (SAS) AF: 0.667 AC: 3212 AN: 4814

European-Finnish (FIN) AF: 0.543 AC: 5717 AN: 10536

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36798 AN: 67956

Other (OTH) AF: 0.507 AC: 1069 AN: 2110

Alfa AF: 0.509 Hom.: 2663

Bravo AF: 0.482

Asia WGS AF: 0.691 AC: 2402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.1
DANN	Benign	0.83
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12822857; hg19: chr12-25369617;