19-17981975-C-T

Variant names:

• chr19-17981975-C-T
• rs74940055
• NM_001386974.1:c.765C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001386974.1(KCNN1):​c.765C>T​(p.Ala255Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,607,894 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (21 hom.)
• Consequence: KCNN1 NM_001386974.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00800
• Publications: 2 publications found

Genes affected

KCNN1 (HGNC:6290): (potassium calcium-activated channel subfamily N member 1) Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. This gene is a member of the KCNN family of potassium channel genes. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-17981975-C-T is Benign according to our data. Variant chr19-17981975-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2649559.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.008 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN1	NM_001386974.1	c.765C>T	p.Ala255Ala	synonymous_variant	Exon 4 of 10	ENST00000684775.1	NP_001373903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN1	ENST00000684775.1	c.765C>T	p.Ala255Ala	synonymous_variant	Exon 4 of 10		NM_001386974.1	ENSP00000507021.1

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00236 AC: 562 AN: 237748 AF XY: 0.00223

Gnomad AFR exome AF: 0.000480

Gnomad AMR exome AF: 0.000453

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00229

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00188

GnomAD4 exome AF: 0.00372 AC: 5412 AN: 1455612 Hom.: 21 Cov.: 33 AF XY: 0.00362 AC XY: 2622 AN XY: 723568

African (AFR) AF: 0.000690 AC: 23 AN: 33324

American (AMR) AF: 0.000480 AC: 21 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39288

South Asian (SAS) AF: 0.00 AC: 0 AN: 85218

European-Finnish (FIN) AF: 0.00229 AC: 120 AN: 52480

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00461 AC: 5115 AN: 1109662

Other (OTH) AF: 0.00219 AC: 132 AN: 60156

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00209 AC XY: 156 AN XY: 74470

African (AFR) AF: 0.000891 AC: 37 AN: 41546

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00423 AC: 288 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00320 Hom.: 1

Bravo AF: 0.00223

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNN1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.8
DANN	Benign	0.86
PhyloP100		0.0080
Mutation Taster		=100/0	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: rs74940055; hg19: chr19-18092784;