rs397517034

Variant names:

• chr12-25250896-C-CGCT
• rs397517034
• NM_033360.4:c.-160_-158dupAGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004985.5(KRAS):​c.-160_-158dupAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 250,204 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: KRAS NM_004985.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.294
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-25250896-C-CGCT is Benign according to our data. Variant chr12-25250896-C-CGCT is described in ClinVar as Likely_benign. ClinVar VariationId is 45111.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00241 (366/152074) while in subpopulation AFR AF = 0.00838 (348/41534). AF 95% confidence interval is 0.00765. There are 2 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 366 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004985.5. 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.-160_-158dupAGC		5_prime_UTR	Exon 1 of 6	NP_203524.1	P01116-1
	KRAS	NM_004985.5	MANE Select	c.-160_-158dupAGC		5_prime_UTR	Exon 1 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.-147_-145dupAGC		5_prime_UTR	Exon 1 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.-160_-158dupAGC		5_prime_UTR	Exon 1 of 6	ENSP00000256078.5	P01116-1
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.-160_-158dupAGC		5_prime_UTR	Exon 1 of 5	ENSP00000308495.3	P01116-2
	KRAS	ENST00000556131.2	TSL:1	c.-160_-158dupAGC		5_prime_UTR	Exon 1 of 3	ENSP00000451856.1	G3V4K2

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 151966 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.000448 AC: 44 AN: 98130 Hom.: 0 Cov.: 0 AF XY: 0.000474 AC XY: 25 AN XY: 52784

African (AFR) AF: 0.0115 AC: 37 AN: 3216

American (AMR) AF: 0.00 AC: 0 AN: 2110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4288

East Asian (EAS) AF: 0.0000931 AC: 1 AN: 10738

South Asian (SAS) AF: 0.00 AC: 0 AN: 4132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1470

Middle Eastern (MID) AF: 0.00193 AC: 1 AN: 518

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64858

Other (OTH) AF: 0.000735 AC: 5 AN: 6800

GnomAD4 genome AF: 0.00241 AC: 366 AN: 152074 Hom.: 2 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74352

African (AFR) AF: 0.00838 AC: 348 AN: 41534

American (AMR) AF: 0.000720 AC: 11 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67920

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00202 Hom.: 0

Bravo AF: 0.00291

Asia WGS AF: 0.000294 AC: 1 AN: 3416

ClinVar

ClinVar submissions

Significance: Likely 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
PhyloP100		0.29
Mutation Taster		=299/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs397517034; hg19: chr12-25403830;