19-43768194-A-G

Variant names:

• chr19-43768194-A-G
• rs3786954
• NM_002250.3:c.1120-487T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002250.3(KCNN4):​c.1120-487T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 152,082 control chromosomes in the GnomAD database, including 6,361 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6361 hom., cov: 33)
• Consequence: KCNN4 NM_002250.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 6 publications found

Genes affected

KCNN4 (HGNC:6293): (potassium calcium-activated channel subfamily N member 4) The protein encoded by this gene is part of a potentially heterotetrameric voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization, which promotes calcium influx. The encoded protein may be part of the predominant calcium-activated potassium channel in T-lymphocytes. This gene is similar to other KCNN family potassium channel genes, but it differs enough to possibly be considered as part of a new subfamily. [provided by RefSeq, Jul 2008]

KCNN4 Gene-Disease associations (from GenCC):

• dehydrated hereditary stomatocytosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296816 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002250.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN4	NM_002250.3	MANE Select	c.1120-487T>C		intron	N/A	NP_002241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN4	ENST00000648319.1	MANE Select	c.1120-487T>C		intron	N/A	ENSP00000496939.1
	KCNN4	ENST00000598836.1	TSL:5	c.331-487T>C		intron	N/A	ENSP00000471900.1
	KCNN4	ENST00000600909.1	TSL:3	c.16-487T>C		intron	N/A	ENSP00000470339.1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 42011 AN: 151964 Hom.: 6353 Cov.: 33

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.286

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.276 AC: 42039 AN: 152082 Hom.: 6361 Cov.: 33 AF XY: 0.272 AC XY: 20241 AN XY: 74364

African (AFR) AF: 0.407 AC: 16865 AN: 41460

American (AMR) AF: 0.193 AC: 2949 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 921 AN: 3468

East Asian (EAS) AF: 0.273 AC: 1412 AN: 5176

South Asian (SAS) AF: 0.168 AC: 811 AN: 4822

European-Finnish (FIN) AF: 0.234 AC: 2470 AN: 10570

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15582 AN: 67976

Other (OTH) AF: 0.283 AC: 598 AN: 2114

Alfa AF: 0.204 Hom.: 851

Bravo AF: 0.281

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.11
DANN	Benign	0.42
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs3786954; hg19: chr19-44272346;