1-5992511-G-A

Position:

• chr1-5992511-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000378097.6(KCNAB2):​c.-330G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0406 in 152,352 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (183 hom., cov: 33)
  • Exomes 𝑓: 0.052 (0 hom.)
• Consequence: KCNAB2 ENST00000378097.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.167

Genes affected

KCNAB2 (HGNC:6229): (potassium voltage-gated channel subfamily A regulatory beta subunit 2) 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, shaker-related subfamily. This member is one of the beta subunits, which are auxiliary proteins associating with functional Kv-alpha subunits. This member alters functional properties of the KCNA4 gene product. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2010]

NPHP4 (HGNC:19104): (nephrocystin 4) This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-5992511-G-A is Benign according to our data. Variant chr1-5992511-G-A is described in ClinVar as [Benign]. Clinvar id is 1258554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNAB2	ENST00000378097.6	c.-330G>A		5_prime_UTR_variant	1/16	1		ENSP00000367337	P4
KCNAB2	ENST00000378111.6	c.-53+955G>A		intron_variant		3		ENSP00000367351
KCNAB2	ENST00000655548.1	c.-53+1468G>A		intron_variant				ENSP00000499615

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6177 AN: 152176 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0616

Gnomad OTH AF: 0.0598

GnomAD4 exome AF: 0.0517 AC: 3 AN: 58 Hom.: 0 Cov.: 0 AF XY: 0.0652 AC XY: 3 AN XY: 46

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0682

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0406 AC: 6176 AN: 152294 Hom.: 183 Cov.: 33 AF XY: 0.0386 AC XY: 2873 AN XY: 74468

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0485

Gnomad4 ASJ AF: 0.0504

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0206

Gnomad4 NFE AF: 0.0616

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0456 Hom.: 20

Bravo AF: 0.0429

Asia WGS AF: 0.00953 AC: 34 AN: 3478

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	clinical testing	GeneDx	May 16, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.1
DANN	Benign	0.86

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: rs61760765; hg19: chr1-6052571;