NM_015656.2:c.25T>C

Variant names:

• chr14-104138747-T-C
• rs555804254
• NM_015656.2:c.25T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015656.2(KIF26A):​c.25T>C​(p.Cys9Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,263,378 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C9G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: KIF26A NM_015656.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0220

Genes affected

KIF26A (HGNC:20226): (kinesin family member 26A) Predicted to enable microtubule binding activity and microtubule motor activity. Predicted to be involved in enteric nervous system development; negative regulation of signal transduction; and regulation of cell growth by extracellular stimulus. Predicted to be located in cytosol. Predicted to be part of kinesin complex. Predicted to be active in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

KIF26A-DT (HGNC:55439): (KIF26A divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025992066).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0006 (91/151692) while in subpopulation AMR AF= 0.00491 (75/15260). AF 95% confidence interval is 0.00402. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF26A	NM_015656.2	c.25T>C	p.Cys9Arg	missense_variant	Exon 1 of 15	ENST00000423312.7	NP_056471.1
KIF26A-DT	NR_158217.1	n.-118A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF26A	ENST00000423312.7	c.25T>C	p.Cys9Arg	missense_variant	Exon 1 of 15	5	NM_015656.2	ENSP00000388241.2
KIF26A	ENST00000697132.1	c.139-296T>C		intron_variant	Intron 1 of 14			ENSP00000513129.1

Frequencies

GnomAD3 genomes AF: 0.000600 AC: 91 AN: 151584 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.000131 AC: 146 AN: 1111686 Hom.: 1 Cov.: 31 AF XY: 0.000140 AC XY: 74 AN XY: 530150

Gnomad4 AFR exome AF: 0.0000439

Gnomad4 AMR exome AF: 0.0100

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00133

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000639

Gnomad4 OTH exome AF: 0.000425

GnomAD4 genome AF: 0.000600 AC: 91 AN: 151692 Hom.: 1 Cov.: 33 AF XY: 0.000566 AC XY: 42 AN XY: 74160

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000393

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000949

Bravo AF: 0.00127

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.25T>C (p.C9R) alteration is located in exon 1 (coding exon 1) of the KIF26A gene. This alteration results from a T to C substitution at nucleotide position 25, causing the cysteine (C) at amino acid position 9 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.94
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.14	T
Polyphen		0.099	B
Vest4		0.23
MutPred		0.39		Gain of MoRF binding (P = 7e-04);
MVP		0.39
MPC		4.9
ClinPred		0.33	T
GERP RS		-1.1
Varity_R		0.64
gMVP		0.39

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: rs555804254; hg19: chr14-104605084;