rs347519

Variant names:

• chr19-43769364-T-C
• rs347519
• NM_002250.3:c.1049+78A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-43769364-T-C
• chr19-43769364-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002250.3(KCNN4):​c.1049+78A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,160,372 control chromosomes in the GnomAD database, including 35,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8043 hom., cov: 32)
  • Exomes 𝑓: 0.22 (27371 hom.)
• Consequence: KCNN4 NM_002250.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.92
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-43769364-T-C is Benign according to our data. Variant chr19-43769364-T-C is described in ClinVar as Benign. ClinVar VariationId is 1260319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN4	NM_002250.3	c.1049+78A>G		intron_variant	Intron 6 of 8	ENST00000648319.1	NP_002241.1
KCNN4	XM_005258882.3	c.953+78A>G		intron_variant	Intron 5 of 7		XP_005258939.1
KCNN4	XM_005258883.3	c.860+78A>G		intron_variant	Intron 6 of 8		XP_005258940.1
KCNN4	XM_047438794.1	c.377+78A>G		intron_variant	Intron 4 of 6		XP_047294750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN4	ENST00000648319.1	c.1049+78A>G		intron_variant	Intron 6 of 8		NM_002250.3	ENSP00000496939.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45818 AN: 151942 Hom.: 8026 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.235 AC: 54485 AN: 231728 AF XY: 0.232

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.281

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.225 AC: 226560 AN: 1008312 Hom.: 27371 Cov.: 13 AF XY: 0.223 AC XY: 115451 AN XY: 517146

African (AFR) AF: 0.497 AC: 12443 AN: 25034

American (AMR) AF: 0.146 AC: 6336 AN: 43422

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 6121 AN: 22224

East Asian (EAS) AF: 0.197 AC: 7386 AN: 37482

South Asian (SAS) AF: 0.174 AC: 13131 AN: 75340

European-Finnish (FIN) AF: 0.233 AC: 10145 AN: 43458

Middle Eastern (MID) AF: 0.249 AC: 1026 AN: 4126

European-Non Finnish (NFE) AF: 0.223 AC: 159018 AN: 711828

Other (OTH) AF: 0.241 AC: 10954 AN: 45398

GnomAD4 genome AF: 0.302 AC: 45868 AN: 152060 Hom.: 8043 Cov.: 32 AF XY: 0.296 AC XY: 22025 AN XY: 74324

African (AFR) AF: 0.497 AC: 20610 AN: 41466

American (AMR) AF: 0.202 AC: 3091 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1408 AN: 5150

South Asian (SAS) AF: 0.170 AC: 816 AN: 4810

European-Finnish (FIN) AF: 0.233 AC: 2463 AN: 10584

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

European-Non Finnish (NFE) AF: 0.228 AC: 15514 AN: 67976

Other (OTH) AF: 0.298 AC: 628 AN: 2108

Alfa AF: 0.193 Hom.: 591

Bravo AF: 0.309

Asia WGS AF: 0.231 AC: 802 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25179167) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.45
DANN	Benign	0.78
PhyloP100		-2.9
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs347519; hg19: chr19-44273516; COSMIC: COSV53455435; COSMIC: COSV53455435;