chr12-25215528-T-C

Variant names:

• chr12-25215528-T-C
• rs4362222
• NM_033360.4:c.483A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PP3_Moderate BP6_Moderate BS1 BS2

The NM_033360.4(KRAS):​c.483A>G​(p.Arg161Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.000274 in 1,612,266 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: KRAS NM_033360.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.79
• Publications: 39 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• 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
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124902899 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: BayesDel_noAF computational evidence supports a deleterious effect, 0.43
• BP6: Variant 12-25215528-T-C is Benign according to our data. Variant chr12-25215528-T-C is described in ClinVar as Benign. ClinVar VariationId is 163759.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0016 (243/152332) while in subpopulation AFR AF = 0.00522 (217/41588). AF 95% confidence interval is 0.00465. There are 1 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 243 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.483A>G	p.Arg161Arg	synonymous	Exon 5 of 6	NP_203524.1	P01116-1
	KRAS	NM_004985.5	MANE Select	c.451-5617A>G		intron	N/A	NP_004976.2
	KRAS	NM_001369786.1		c.483A>G	p.Arg161Arg	synonymous	Exon 5 of 6	NP_001356715.1	P01116-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.483A>G	p.Arg161Arg	synonymous	Exon 5 of 6	ENSP00000256078.5	P01116-1
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.451-5617A>G		intron	N/A	ENSP00000308495.3	P01116-2
	KRAS	ENST00000685328.1		c.451-5617A>G		intron	N/A	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000136 AC: 198 AN: 1459934 Hom.: 0 Cov.: 30 AF XY: 0.000114 AC XY: 83 AN XY: 726416

African (AFR) AF: 0.00478 AC: 160 AN: 33444

American (AMR) AF: 0.000246 AC: 11 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110418

Other (OTH) AF: 0.000365 AC: 22 AN: 60326

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152332 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74488

African (AFR) AF: 0.00522 AC: 217 AN: 41588

American (AMR) AF: 0.00137 AC: 21 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000812 Hom.: 0

Bravo AF: 0.00214

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	23
PhyloP100		5.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4362222; hg19: chr12-25368462;