rs20455

Positions:

• chr6-39357302-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145027.6(KIF6):​c.2155T>C​(p.Trp719Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,611,174 control chromosomes in the GnomAD database, including 129,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.49 (21098 hom., cov: 31)
  • Exomes 𝑓: 0.38 (107970 hom.)
• Consequence: KIF6 NM_145027.6 missense
• Clinical Significance: drug response reviewed by expert panel O:1
• Conservation: PhyloP100: 0.0610

Genes affected

KIF6 (HGNC:21202): (kinesin family member 6) This gene encodes a member of a family of molecular motors which are involved in intracellular transport of protein complexes, membrane organelles, and messenger ribonucleic acid along microtubules. Kinesins function as homodimeric molecules with two N-terminal head domains that move along microtubules and two C-terminal tail domains that interact with the transported cargo, either directly or indirectly, through adapter molecules. This gene is ubiquitously expressed in coronary arteries and other vascular tissue. A naturally occurring mutation in this gene is associated with coronary heart disease. [provided by RefSeq, May 2017]

LOC107986594 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2283395E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF6	NM_145027.6	c.2155T>C	p.Trp719Arg	missense_variant	19/23	ENST00000287152.12	NP_659464.3
LOC107986594	XR_001744111.2	n.219+5354A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF6	ENST00000287152.12	c.2155T>C	p.Trp719Arg	missense_variant	19/23	2	NM_145027.6	ENSP00000287152	P1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74283 AN: 151892 Hom.: 21067 Cov.: 31

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.468

GnomAD3 exomes AF: 0.405 AC: 101846 AN: 251262 Hom.: 22539 AF XY: 0.400 AC XY: 54334 AN XY: 135788

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.336

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.467

Gnomad SAS exome AF: 0.435

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.376 AC: 548109 AN: 1459164 Hom.: 107970 Cov.: 32 AF XY: 0.376 AC XY: 273110 AN XY: 726034

Gnomad4 AFR exome AF: 0.811

Gnomad4 AMR exome AF: 0.344

Gnomad4 ASJ exome AF: 0.340

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.345

Gnomad4 NFE exome AF: 0.357

Gnomad4 OTH exome AF: 0.404

GnomAD4 genome AF: 0.489 AC: 74366 AN: 152010 Hom.: 21098 Cov.: 31 AF XY: 0.485 AC XY: 36000 AN XY: 74288

Gnomad4 AFR AF: 0.798

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.339

Gnomad4 EAS AF: 0.477

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.347

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.470

Alfa AF: 0.393 Hom.: 22248

Bravo AF: 0.504

TwinsUK AF: 0.345 AC: 1278

ALSPAC AF: 0.356 AC: 1372

ESP6500AA AF: 0.782 AC: 3444

ESP6500EA AF: 0.358 AC: 3078

ExAC AF: 0.417 AC: 50687

Asia WGS AF: 0.512 AC: 1782 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.371

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: reviewed by expert panel

Submissions by phenotype

pravastatin response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	2.0
DANN	Benign	0.30
DEOGEN2	Benign	0.0012	T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00095	N
LIST_S2	Benign	0.032	T;T;T;T
MetaRNN	Benign	8.2e-7	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.81	N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.17	T
PROVEAN	Benign	1.5	N;N;N;.
REVEL	Benign	0.23
Sift	Benign	0.69	T;T;T;.
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.016
MutPred		0.087		Gain of solvent accessibility (P = 0.0584);.;.;.;
MPC		0.11
ClinPred		0.00041	T
GERP RS		0.53
Varity_R		0.051
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs20455; hg19: chr6-39325078; COSMIC: COSV54671370; COSMIC: COSV54671370;