1-5992521-G-A

Position:

• chr1-5992521-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.-320G>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 0.836 in 152,302 control chromosomes in the GnomAD database, including 53,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53651 hom., cov: 34)
  • Exomes 𝑓: 0.79 (31 hom.)
• Consequence: KCNAB2 ENST00000378097.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.326

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=-0.82).
• BP6: Variant 1-5992521-G-A is Benign according to our data. Variant chr1-5992521-G-A is described in ClinVar as [Benign]. Clinvar id is 1252161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.969 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.-320G>A		5_prime_UTR_variant	1/16	1		ENSP00000367337	P4
KCNAB2	ENST00000378111.6	c.-53+965G>A		intron_variant		3		ENSP00000367351
KCNAB2	ENST00000655548.1	c.-53+1478G>A		intron_variant				ENSP00000499615

Frequencies

GnomAD3 genomes AF: 0.836 AC: 127135 AN: 152078 Hom.: 53596 Cov.: 34

Gnomad AFR AF: 0.945

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.797

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.864

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.835

GnomAD4 exome AF: 0.792 AC: 84 AN: 106 Hom.: 31 Cov.: 0 AF XY: 0.800 AC XY: 64 AN XY: 80

Gnomad4 AFR exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.772

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.836 AC: 127247 AN: 152196 Hom.: 53651 Cov.: 34 AF XY: 0.840 AC XY: 62500 AN XY: 74412

Gnomad4 AFR AF: 0.945

Gnomad4 AMR AF: 0.859

Gnomad4 ASJ AF: 0.797

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.864

Gnomad4 FIN AF: 0.786

Gnomad4 NFE AF: 0.762

Gnomad4 OTH AF: 0.830

Alfa AF: 0.716 Hom.: 2029

Bravo AF: 0.847

Asia WGS AF: 0.908 AC: 3155 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.74

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: rs806109; hg19: chr1-6052581;