3-156523857-A-C

Variant names:

• chr3-156523857-A-C
• rs1718117284
• NM_172160.3:c.991A>C

Variant summary

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

The NM_172160.3(KCNAB1):​c.991A>C​(p.Ser331Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNAB1 NM_172160.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13

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]

ENSG00000272990 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNAB1	NM_172160.3	c.991A>C	p.Ser331Arg	missense_variant	Exon 12 of 14	ENST00000490337.6	NP_751892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNAB1	ENST00000490337.6	c.991A>C	p.Ser331Arg	missense_variant	Exon 12 of 14	1	NM_172160.3	ENSP00000419952.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.991A>C (p.S331R) alteration is located in exon 12 (coding exon 12) of the KCNAB1 gene. This alteration results from a A to C substitution at nucleotide position 991, causing the serine (S) at amino acid position 331 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.;.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.78	N;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.1	D;D;D;.;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.11	T;T;T;.;T;T
Sift4G	Benign	0.066	T;T;T;T;T;T
Polyphen		0.94	P;P;P;.;.;P
Vest4		0.69
MutPred		0.51		Gain of MoRF binding (P = 0.0175);.;.;.;.;.;
MVP		0.65
MPC		0.69
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.63
gMVP		0.90

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: rs1718117284; hg19: chr3-156241646;