14-104139094-C-T

Variant names:

• chr14-104139094-C-T
• rs2037611709
• NM_015656.2:c.94C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015656.2(KIF26A):​c.94C>T​(p.Pro32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,311,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P32A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KIF26A NM_015656.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.850
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations

  Inheritance: AR Classification: STRONG Submitted by: ClinGen
• cortical dysplasia, complex, with other brain malformations 11

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Baylor College of Medicine Research Center, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36177254).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015656.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF26A	NM_015656.2	MANE Select	c.94C>T	p.Pro32Ser	missense	Exon 2 of 15	NP_056471.1	Q9ULI4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF26A	ENST00000423312.7	TSL:5 MANE Select	c.94C>T	p.Pro32Ser	missense	Exon 2 of 15	ENSP00000388241.2	Q9ULI4
	KIF26A	ENST00000315264.7	TSL:1	c.-324C>T		5_prime_UTR	Exon 1 of 14	ENSP00000325452.7	C9JFF0
	KIF26A	ENST00000697132.1		c.190C>T	p.Pro64Ser	missense	Exon 2 of 15	ENSP00000513129.1	A0A8V8TM02

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1311776 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644740

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25750

American (AMR) AF: 0.00 AC: 0 AN: 21670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22478

East Asian (EAS) AF: 0.0000349 AC: 1 AN: 28648

South Asian (SAS) AF: 0.00 AC: 0 AN: 67956

European-Finnish (FIN) AF: 0.0000224 AC: 1 AN: 44556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3918

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1042778

Other (OTH) AF: 0.00 AC: 0 AN: 54022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.85
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.26
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.072	T
Polyphen		0.92	P
Vest4		0.15
MutPred		0.26		Gain of phosphorylation at P32 (P = 0.0042)
MVP		0.86
MPC		3.4
ClinPred		0.58	D
GERP RS		1.9
PromoterAI		-0.0028	Neutral
Varity_R		0.084
gMVP		0.33
Mutation Taster		=90/10	polymorphism

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: rs2037611709; hg19: chr14-104605431;