NM_001386974.1:c.110C>T

Variant names:

• chr19-17973998-C-T
• rs376519329
• NM_001386974.1:c.110C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001386974.1(KCNN1):​c.110C>T​(p.Pro37Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,588,234 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (1 hom.)
• Consequence: KCNN1 NM_001386974.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008320063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN1	NM_001386974.1	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 10	ENST00000684775.1	NP_001373903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN1	ENST00000684775.1	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 10		NM_001386974.1	ENSP00000507021.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000110 AC: 22 AN: 199314 AF XY: 0.0000999

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.0000344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000494 AC: 71 AN: 1435914 Hom.: 1 Cov.: 31 AF XY: 0.0000491 AC XY: 35 AN XY: 712516

African (AFR) AF: 0.00133 AC: 44 AN: 32990

American (AMR) AF: 0.00 AC: 0 AN: 40046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 38574

South Asian (SAS) AF: 0.000119 AC: 10 AN: 83814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1100892

Other (OTH) AF: 0.0000673 AC: 4 AN: 59392

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74482

African (AFR) AF: 0.00123 AC: 51 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000351

ESP6500AA AF: 0.000279 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000761 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.110C>T (p.P37L) alteration is located in exon 3 (coding exon 1) of the KCNN1 gene. This alteration results from a C to T substitution at nucleotide position 110, causing the proline (P) at amino acid position 37 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.8
DANN	Benign	0.61
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.065	N;.;.
PhyloP100		1.8
PrimateAI	Uncertain	0.54	T
REVEL	Benign	0.10
Sift4G	Benign	0.72	T;D;T
Polyphen		0.0	B;.;.
Vest4		0.12
MVP		0.068
MPC		0.51
ClinPred		0.045	T
GERP RS		0.0091
Varity_R		0.058
gMVP		0.23
Mutation Taster		=98/2	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: rs376519329; hg19: chr19-18084807;