1-5992521-G-A

Variant names:

• chr1-5992521-G-A
• rs806109
• ENST00000378097.6:c.-320G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

NPHP4 Gene-Disease associations (from GenCC):

• nephronophthisis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000378097.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.-316C>T		upstream_gene	N/A	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.-1365C>T		upstream_gene	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.-1545C>T		upstream_gene	N/A	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNAB2	ENST00000378097.6	TSL:1	c.-320G>A		5_prime_UTR	Exon 1 of 16	ENSP00000367337.1	Q13303-1
	NPHP4	ENST00000923561.1		c.-39+841C>T		intron	N/A	ENSP00000593620.1
	NPHP4	ENST00000923562.1		c.-39+841C>T		intron	N/A	ENSP00000593621.1

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

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 1.00 AC: 4 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.772 AC: 71 AN: 92

Other (OTH) AF: 1.00 AC: 4 AN: 4

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

African (AFR) AF: 0.945 AC: 39278 AN: 41554

American (AMR) AF: 0.859 AC: 13145 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 2764 AN: 3470

East Asian (EAS) AF: 0.991 AC: 5111 AN: 5156

South Asian (SAS) AF: 0.864 AC: 4173 AN: 4830

European-Finnish (FIN) AF: 0.786 AC: 8317 AN: 10588

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51783 AN: 67976

Other (OTH) AF: 0.830 AC: 1756 AN: 2116

Alfa AF: 0.716 Hom.: 2029

Bravo AF: 0.847

Asia WGS AF: 0.908 AC: 3155 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.74
PhyloP100		-0.33
PromoterAI		0.050	Neutral
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs806109; hg19: chr1-6052581;