3-156523854-G-T

Position:

• chr3-156523854-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172160.3(KCNAB1):​c.988G>T​(p.Val330Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,272 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNAB1 NM_172160.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0850

Genes affected

KCNAB1 (HGNC:6228): (potassium voltage-gated channel subfamily A regulatory beta subunit 1) Potassium 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 includes distinct isoforms which are encoded by alternatively spliced transcript variants of this gene. Some of these isoforms are beta subunits, which form heteromultimeric complexes with alpha subunits and modulate the activity of the pore-forming alpha subunits. [provided by RefSeq, Apr 2015]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061805725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNAB1	NM_172160.3	c.988G>T	p.Val330Leu	missense_variant	12/14	ENST00000490337.6	NP_751892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNAB1	ENST00000490337.6	c.988G>T	p.Val330Leu	missense_variant	12/14	1	NM_172160.3	ENSP00000419952
	ENST00000609190.1	n.394C>A		non_coding_transcript_exon_variant	1/1
	ENST00000661961.1	n.39-15610G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461272 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726984

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 09, 2021

The c.988G>T (p.V330L) alteration is located in exon 12 (coding exon 12) of the KCNAB1 gene. This alteration results from a G to T substitution at nucleotide position 988, causing the valine (V) at amino acid position 330 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	0.079
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.043	T;.;.;.;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.062	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.70	N;.;.;.;.;.
MutationTaster	Benign	0.88	N;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.72	N;N;N;.;N;N
REVEL	Benign	0.12
Sift	Benign	0.60	T;T;T;.;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;B
Vest4		0.12
MutPred		0.45		Loss of MoRF binding (P = 0.0964);.;.;.;.;.;
MVP		0.25
MPC		0.52
ClinPred		0.49	T
GERP RS		4.8
Varity_R		0.045
gMVP		0.52

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: rs866610957; hg19: chr3-156241643;