19-43769804-A-T

Variant names:

• chr19-43769804-A-T
• rs1057519077
• NM_002250.3:c.845T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_002250.3(KCNN4):​c.845T>A​(p.Val282Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V282M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNN4 NM_002250.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.18
• Publications: 8 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-43769805-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 372185.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 19-43769804-A-T is Pathogenic according to our data. Variant chr19-43769804-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 372186.Status of the report is criteria_provided_single_submitter, 1 stars.

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.845T>A	p.Val282Glu	missense	Exon 5 of 9	NP_002241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN4	ENST00000648319.1	MANE Select	c.845T>A	p.Val282Glu	missense	Exon 5 of 9	ENSP00000496939.1
	KCNN4	ENST00000598836.1	TSL:5	c.23T>A	p.Val8Glu	missense	Exon 1 of 5	ENSP00000471900.1
	KCNN4	ENST00000599720.5	TSL:5	n.*115T>A		non_coding_transcript_exon	Exon 3 of 7	ENSP00000472513.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dehydrated hereditary stomatocytosis 2 Pathogenic:2

Sep 13, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 11, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.95
MutPred		0.80		Loss of stability (P = 0.1029)
MVP		0.92
MPC		1.8
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs1057519077; hg19: chr19-44273956;