rs112735799

Variant names:

• chr20-49373723-G-A
• rs112735799
• NM_004975.4:c.1837C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004975.4(KCNB1):​c.1837C>T​(p.Pro613Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,128 control chromosomes in the GnomAD database, including 296 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P613P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 32)
  • Exomes 𝑓: 0.017 (282 hom.)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.83

Genes affected

KCNB1 (HGNC:6231): (potassium voltage-gated channel subfamily B member 1) 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, shab-related subfamily. This member is a delayed rectifier potassium channel and its activity is modulated by some other family members. [provided by RefSeq, Jul 2008]

ENSG00000290421 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003902465).
• BP6: Variant 20-49373723-G-A is Benign according to our data. Variant chr20-49373723-G-A is described in ClinVar as [Benign]. Clinvar id is 383226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1860/152250) while in subpopulation NFE AF = 0.0186 (1262/68018). AF 95% confidence interval is 0.0177. There are 14 homozygotes in GnomAd4. There are 873 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1860 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.1837C>T	p.Pro613Ser	missense_variant	Exon 2 of 2	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.1837C>T	p.Pro613Ser	missense_variant	Exon 3 of 3		XP_011527101.1
LOC105372649	XR_001754659.2	n.1201+41699G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.1837C>T	p.Pro613Ser	missense_variant	Exon 2 of 2	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.1837C>T	p.Pro613Ser	missense_variant	Exon 3 of 3	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.97-74340C>T		intron_variant	Intron 1 of 2	5		ENSP00000489908.1
ENSG00000290421	ENST00000637341.1	n.206+41699G>A		intron_variant	Intron 2 of 7	5

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1860 AN: 152132 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0135 AC: 3378 AN: 251074 AF XY: 0.0133

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0173 AC: 25294 AN: 1461878 Hom.: 282 Cov.: 33 AF XY: 0.0166 AC XY: 12088 AN XY: 727242

Gnomad4 AFR exome AF: 0.00302 AC: 101 AN: 33480

Gnomad4 AMR exome AF: 0.0108 AC: 481 AN: 44724

Gnomad4 ASJ exome AF: 0.00386 AC: 101 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.0000580 AC: 5 AN: 86258

Gnomad4 FIN exome AF: 0.0266 AC: 1423 AN: 53412

Gnomad4 NFE exome AF: 0.0201 AC: 22324 AN: 1112006

Gnomad4 Remaining exome AF: 0.0139 AC: 839 AN: 60396

GnomAD4 genome AF: 0.0122 AC: 1860 AN: 152250 Hom.: 14 Cov.: 32 AF XY: 0.0117 AC XY: 873 AN XY: 74442

Gnomad4 AFR AF: 0.00335 AC: 0.00334521 AN: 0.00334521

Gnomad4 AMR AF: 0.00811 AC: 0.00810563 AN: 0.00810563

Gnomad4 ASJ AF: 0.00346 AC: 0.00345821 AN: 0.00345821

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0265 AC: 0.0265194 AN: 0.0265194

Gnomad4 NFE AF: 0.0186 AC: 0.0185539 AN: 0.0185539

Gnomad4 OTH AF: 0.0137 AC: 0.0137441 AN: 0.0137441

Alfa AF: 0.0161 Hom.: 85

Bravo AF: 0.0115

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0177 AC: 152

ExAC AF: 0.0141 AC: 1715

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0175

EpiControl AF: 0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 20, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 04, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Developmental and epileptic encephalopathy, 26 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.67	.;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.11
Sift	Benign	0.11	T;.
Sift4G	Benign	0.11	T;T
Polyphen		0.0	B;B
Vest4		0.035
MPC		0.19
ClinPred		0.0060	T
GERP RS		1.2
Varity_R		0.048
gMVP		0.31
Mutation Taster		=99/1	polymorphism (auto)

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: rs112735799; hg19: chr20-47990260; COSMIC: COSV99056961; COSMIC: COSV99056961;