20-49373469-G-C

Position:

• chr20-49373469-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004975.4(KCNB1):​c.2091C>G​(p.Asn697Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNB1. . Gene score misZ 4.269 (greater than the threshold 3.09). Trascript score misZ 5.3923 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 26.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15652451).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.2091C>G	p.Asn697Lys	missense_variant	2/2	ENST00000371741.6	NP_004966.1
LOC105372649	XR_001754659.2	n.1201+41445G>C		intron_variant, non_coding_transcript_variant
KCNB1	XM_011528799.3	c.2091C>G	p.Asn697Lys	missense_variant	3/3		XP_011527101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.2091C>G	p.Asn697Lys	missense_variant	2/2	1	NM_004975.4	ENSP00000360806	P1
KCNB1	ENST00000635465.1	c.2091C>G	p.Asn697Lys	missense_variant	3/3	1		ENSP00000489193	P1
	ENST00000637341.1	n.206+41445G>C		intron_variant, non_coding_transcript_variant		5
KCNB1	ENST00000635878.1	c.97-74086C>G		intron_variant		5		ENSP00000489908

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2017

A variant of uncertain significance has been identified in the KCN1B gene. The N697K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N697K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N697K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.67	N;.
REVEL	Benign	0.10
Sift	Benign	0.071	T;.
Sift4G	Benign	0.49	T;T
Polyphen		0.030	B;B
Vest4		0.18
MutPred		0.50		Gain of ubiquitination at N697 (P = 0.0177);Gain of ubiquitination at N697 (P = 0.0177);
MVP		0.47
MPC		0.24
ClinPred		0.14	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.33

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: rs746382408; hg19: chr20-47990006;