chr17-27582790-C-T

Variant names:

• chr17-27582790-C-T
• rs2293180
• NM_001394583.1:c.665C>T

Variant summary

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

The NM_001394583.1(KSR1):​c.665C>T​(p.Ala222Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,452 control chromosomes in the GnomAD database, including 15,654 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1624 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14030 hom.)
• Consequence: KSR1 NM_001394583.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.584
• Publications: 20 publications found

Genes affected

KSR1 (HGNC:6465): (kinase suppressor of ras 1) Enables 14-3-3 protein binding activity; ATP binding activity; and protein C-terminus binding activity. Involved in positive regulation of MAPK cascade. Located in endoplasmic reticulum and membrane. Part of protein-containing complex. Implicated in breast adenocarcinoma. Biomarker of breast cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.005291939).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KSR1	NM_001394583.1	c.665C>T	p.Ala222Val	missense_variant	Exon 4 of 21	ENST00000644974.2	NP_001381512.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KSR1	ENST00000644974.2	c.665C>T	p.Ala222Val	missense_variant	Exon 4 of 21		NM_001394583.1	ENSP00000494552.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21048 AN: 151986 Hom.: 1620 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0943

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.159 AC: 39262 AN: 247710 AF XY: 0.156

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.0905

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.132 AC: 193082 AN: 1461348 Hom.: 14030 Cov.: 33 AF XY: 0.133 AC XY: 96985 AN XY: 727000

African (AFR) AF: 0.141 AC: 4706 AN: 33474

American (AMR) AF: 0.273 AC: 12187 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5220 AN: 26112

East Asian (EAS) AF: 0.245 AC: 9743 AN: 39692

South Asian (SAS) AF: 0.190 AC: 16395 AN: 86240

European-Finnish (FIN) AF: 0.0924 AC: 4931 AN: 53348

Middle Eastern (MID) AF: 0.139 AC: 799 AN: 5748

European-Non Finnish (NFE) AF: 0.118 AC: 130840 AN: 1111720

Other (OTH) AF: 0.137 AC: 8261 AN: 60360

GnomAD4 genome AF: 0.138 AC: 21057 AN: 152104 Hom.: 1624 Cov.: 32 AF XY: 0.140 AC XY: 10380 AN XY: 74358

African (AFR) AF: 0.134 AC: 5541 AN: 41484

American (AMR) AF: 0.230 AC: 3523 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 653 AN: 3468

East Asian (EAS) AF: 0.203 AC: 1048 AN: 5152

South Asian (SAS) AF: 0.194 AC: 932 AN: 4808

European-Finnish (FIN) AF: 0.0943 AC: 1001 AN: 10610

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7914 AN: 67976

Other (OTH) AF: 0.154 AC: 324 AN: 2110

Alfa AF: 0.132 Hom.: 3380

Bravo AF: 0.151

TwinsUK AF: 0.121 AC: 448

ALSPAC AF: 0.117 AC: 450

ESP6500AA AF: 0.129 AC: 541

ESP6500EA AF: 0.118 AC: 990

ExAC AF: 0.153 AC: 18484

Asia WGS AF: 0.182 AC: 634 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.118

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;T;.;.;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.86	D;D;D;D;.;D
MetaRNN	Benign	0.0053	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.58
PrimateAI	Benign	0.37	T
REVEL	Benign	0.051
Sift4G	Benign	0.53	.;T;T;T;T;.
Vest4		0.041
MPC		0.38
ClinPred		0.0017	T
GERP RS		1.2
PromoterAI		0.018	Neutral
gMVP		0.13
Mutation Taster		=97/3	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: rs2293180; hg19: chr17-25909816; COSMIC: COSV52037071; COSMIC: COSV52037071;