14-104152096-C-T

Variant names:

• chr14-104152096-C-T
• rs763499680
• ENST00000315264:c.-48C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The ENST00000315264(KIF26A):​c.-48C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: KIF26A ENST00000315264 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39588585).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000024 (35/1460258) while in subpopulation MID AF= 0.000693 (4/5768). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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.370C>T	p.Arg124Cys	missense_variant	Exon 3 of 15	ENST00000423312.7	NP_056471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF26A	ENST00000315264	c.-48C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 14	1		ENSP00000325452.7
KIF26A	ENST00000423312.7	c.370C>T	p.Arg124Cys	missense_variant	Exon 3 of 15	5	NM_015656.2	ENSP00000388241.2
KIF26A	ENST00000315264	c.-48C>T		5_prime_UTR_variant	Exon 2 of 14	1		ENSP00000325452.7
KIF26A	ENST00000697132.1	c.466C>T	p.Arg156Cys	missense_variant	Exon 3 of 15			ENSP00000513129.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000246 AC: 6 AN: 243982 Hom.: 0 AF XY: 0.0000374 AC XY: 5 AN XY: 133762

Gnomad AFR exome AF: 0.0000683

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460258 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726438

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.370C>T (p.R124C) alteration is located in exon 3 (coding exon 3) of the KIF26A gene. This alteration results from a C to T substitution at nucleotide position 370, causing the arginine (R) at amino acid position 124 to be replaced by a cysteine (C). 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	Benign	0.093
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0010	B
Vest4		0.47
MutPred		0.44		Loss of loop (P = 0.2237);
MVP		0.73
MPC		0.34
ClinPred		0.58	D
GERP RS		3.3
Varity_R		0.36
gMVP		0.42

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: rs763499680; hg19: chr14-104618433;