19-43767628-G-T

Variant names:

• chr19-43767628-G-T
• rs954068767
• NM_002250.3:c.1199C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002250.3(KCNN4):​c.1199C>A​(p.Ala400Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A400V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KCNN4 NM_002250.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• Publications: 2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1571402).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN4	NM_002250.3	MANE Select	c.1199C>A	p.Ala400Glu	missense	Exon 8 of 9	NP_002241.1	O15554

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN4	ENST00000648319.1	MANE Select	c.1199C>A	p.Ala400Glu	missense	Exon 8 of 9	ENSP00000496939.1	O15554
	KCNN4	ENST00000969512.1		c.1259C>A	p.Ala420Glu	missense	Exon 8 of 9	ENSP00000639571.1
	KCNN4	ENST00000852946.1		c.1241C>A	p.Ala414Glu	missense	Exon 9 of 10	ENSP00000523005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251438 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Benign	0.23
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.16	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.64	N
PhyloP100		3.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	2.5	N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.35		Loss of helix (P = 0.0093)
MVP		0.93
MPC		0.73
ClinPred		0.24	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.34
Mutation Taster		=61/39	polymorphism

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: rs954068767; hg19: chr19-44271780;