NM_145027.6:c.2155T>C

Variant names:

• chr6-39357302-A-G
• rs20455
• NM_145027.6:c.2155T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• 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
• Publications: 134 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KIF6	NM_145027.6	c.2155T>C	p.Trp719Arg	missense_variant	Exon 19 of 23	ENST00000287152.12	NP_659464.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF6	ENST00000287152.12	c.2155T>C	p.Trp719Arg	missense_variant	Exon 19 of 23	2	NM_145027.6	ENSP00000287152.7

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

GnomAD2 exomes AF: 0.405 AC: 101846 AN: 251262 AF XY: 0.400

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 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

African (AFR) AF: 0.811 AC: 27109 AN: 33412

American (AMR) AF: 0.344 AC: 15356 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 8875 AN: 26120

East Asian (EAS) AF: 0.477 AC: 18909 AN: 39680

South Asian (SAS) AF: 0.428 AC: 36887 AN: 86146

European-Finnish (FIN) AF: 0.345 AC: 18432 AN: 53396

Middle Eastern (MID) AF: 0.414 AC: 2387 AN: 5764

European-Non Finnish (NFE) AF: 0.357 AC: 395811 AN: 1109676

Other (OTH) AF: 0.404 AC: 24343 AN: 60290

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

African (AFR) AF: 0.798 AC: 33085 AN: 41462

American (AMR) AF: 0.385 AC: 5875 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1176 AN: 3472

East Asian (EAS) AF: 0.477 AC: 2454 AN: 5142

South Asian (SAS) AF: 0.445 AC: 2143 AN: 4818

European-Finnish (FIN) AF: 0.347 AC: 3667 AN: 10578

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24541 AN: 67962

Other (OTH) AF: 0.470 AC: 992 AN: 2112

Alfa AF: 0.424 Hom.: 38444

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

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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;.;.;.
PhyloP100		0.061
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
Mutation Taster		=99/1	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: rs20455; hg19: chr6-39325078; COSMIC: COSV54671370; COSMIC: COSV54671370;