chr3-156120696-G-C

Position:

• chr3-156120696-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172160.3(KCNAB1):​c.85G>C​(p.Ala29Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,614,230 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: KCNAB1 NM_172160.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.84

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029160678).
• BP6: Variant 3-156120696-G-C is Benign according to our data. Variant chr3-156120696-G-C is described in ClinVar as [Benign]. Clinvar id is 785070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1630/152338) while in subpopulation AFR AF= 0.0368 (1532/41576). AF 95% confidence interval is 0.0353. There are 31 homozygotes in gnomad4. There are 789 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNAB1	NM_172160.3	c.85G>C	p.Ala29Pro	missense_variant	1/14	ENST00000490337.6	NP_751892.1
KCNAB1	NM_001308217.1	c.85G>C	p.Ala29Pro	missense_variant	1/13		NP_001295146.1
KCNAB1	XM_017007174.3	c.85G>C	p.Ala29Pro	missense_variant	1/9		XP_016862663.1
KCNAB1	XM_017007171.3	c.29+2357G>C		intron_variant			XP_016862660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNAB1	ENST00000490337.6	c.85G>C	p.Ala29Pro	missense_variant	1/14	1	NM_172160.3	ENSP00000419952

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1628 AN: 152220 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00280 AC: 703 AN: 251472 Hom.: 15 AF XY: 0.00213 AC XY: 289 AN XY: 135910

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00111 AC: 1616 AN: 1461892 Hom.: 28 Cov.: 31 AF XY: 0.000950 AC XY: 691 AN XY: 727246

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.0107 AC: 1630 AN: 152338 Hom.: 31 Cov.: 33 AF XY: 0.0106 AC XY: 789 AN XY: 74480

Gnomad4 AFR AF: 0.0368

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00178 Hom.: 4

Bravo AF: 0.0120

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0374 AC: 165

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00358 AC: 435

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.069
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.073	T;T
Polyphen		0.021	B;B
Vest4		0.18
MVP		0.37
MPC		0.76
ClinPred		0.025	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.30

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72558048; hg19: chr3-155838485;