rs748597382

Positions:

• chr20-49373240-G-C
• chr20-49373240-G-T

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.2320C>G​(p.Pro774Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P774T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.00

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=0.184486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNB1	NM_004975.4	c.2320C>G	p.Pro774Ala	missense_variant	2/2	ENST00000371741.6
LOC105372649	XR_001754659.2	n.1201+41216G>C		intron_variant, non_coding_transcript_variant
KCNB1	XM_011528799.3	c.2320C>G	p.Pro774Ala	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNB1	ENST00000371741.6	c.2320C>G	p.Pro774Ala	missense_variant	2/2	1	NM_004975.4	P1
KCNB1	ENST00000635465.1	c.2320C>G	p.Pro774Ala	missense_variant	3/3	1		P1
	ENST00000637341.1	n.206+41216G>C		intron_variant, non_coding_transcript_variant		5
KCNB1	ENST00000635878.1	c.97-73857C>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.70	N;.
REVEL	Benign	0.27
Sift	Benign	0.10	T;.
Sift4G	Benign	0.091	T;T
Polyphen		0.58	P;P
Vest4		0.16
MutPred		0.17		Loss of glycosylation at P774 (P = 0.0148);Loss of glycosylation at P774 (P = 0.0148);
MVP		0.53
MPC		0.19
ClinPred		0.47	T
GERP RS		4.5
Varity_R		0.083
gMVP		0.39

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: rs748597382; hg19: chr20-47989777;