1-6040609-C-T

Position:

• chr1-6040609-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_003636.4(KCNAB2):​c.41C>T​(p.Ser14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,788 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNAB2 NM_003636.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

Genes affected

KCNAB2 (HGNC:6229): (potassium voltage-gated channel subfamily A regulatory beta subunit 2) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member is one of the beta subunits, which are auxiliary proteins associating with functional Kv-alpha subunits. This member alters functional properties of the KCNA4 gene product. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2010]

KCNAB2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity KCAB2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29987872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNAB2	NM_001199860.2	c.41C>T	p.Ser14Leu	missense_variant	2/16		NP_001186789.1
KCNAB2	NM_001199861.2	c.41C>T	p.Ser14Leu	missense_variant	2/16		NP_001186790.1
KCNAB2	NM_003636.4	c.41C>T	p.Ser14Leu	missense_variant	2/16		NP_003627.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNAB2	ENST00000341524.6	c.41C>T	p.Ser14Leu	missense_variant	2/17	1		ENSP00000340824.2
KCNAB2	ENST00000378097.6	c.41C>T	p.Ser14Leu	missense_variant	2/16	1		ENSP00000367337.1
KCNAB2	ENST00000352527.6	c.41C>T	p.Ser14Leu	missense_variant	2/15	1		ENSP00000318772.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461788 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.41C>T (p.S14L) alteration is located in exon 2 (coding exon 1) of the KCNAB2 gene. This alteration results from a C to T substitution at nucleotide position 41, causing the serine (S) at amino acid position 14 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;T;.;T;.;T;T;T;.;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	.;.;.;D;D;D;.;D;D;.
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	.;N;N;.;N;N;.;.;N;N
PROVEAN	Benign	-0.32	N;N;N;D;N;N;N;N;.;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D;T;D;T;D;D;T;.;D
Sift4G	Uncertain	0.0070	D;T;T;D;T;T;D;T;D;T
Polyphen		0.83, 0.74	.;P;P;.;P;P;.;.;.;P
Vest4		0.75
MutPred		0.33		Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);Loss of phosphorylation at S14 (P = 0.0095);
MVP		0.82
ClinPred		0.79	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1258943216; hg19: chr1-6100669; COSMIC: COSV99379705; COSMIC: COSV99379705;