12-5044717-C-T

Variant names:

• chr12-5044717-C-T
• rs12720444
• NM_002234.4:c.570C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_002234.4(KCNA5):​c.570C>T​(p.Asn190Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 1,614,142 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (22 hom.)
• Consequence: KCNA5 NM_002234.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.537
• Publications: 5 publications found

Genes affected

KCNA5 (HGNC:6224): (potassium voltage-gated channel subfamily A member 5) Potassium channels represent the most complex class of voltage-gated ino channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Defects in this gene are a cause of familial atrial fibrillation type 7 (ATFB7). [provided by RefSeq, May 2012]

KCNA5 Gene-Disease associations (from GenCC):

• atrial fibrillation, familial, 7

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-5044717-C-T is Benign according to our data. Variant chr12-5044717-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469595.
• BP7: Synonymous conserved (PhyloP=-0.537 with no splicing effect.
• BS2: High AC in GnomAd4 at 529 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002234.4. 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
	KCNA5	NM_002234.4	MANE Select	c.570C>T	p.Asn190Asn	synonymous	Exon 1 of 1	NP_002225.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA5	ENST00000252321.5	TSL:6 MANE Select	c.570C>T	p.Asn190Asn	synonymous	Exon 1 of 1	ENSP00000252321.3	P22460-1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152152 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00830

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00360 AC: 905 AN: 251344 AF XY: 0.00367

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00786

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00488 AC: 7134 AN: 1461872 Hom.: 22 Cov.: 32 AF XY: 0.00467 AC XY: 3394 AN XY: 727236

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26136

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

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00732 AC: 391 AN: 53402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00573 AC: 6368 AN: 1112008

Other (OTH) AF: 0.00306 AC: 185 AN: 60396

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152270 Hom.: 1 Cov.: 33 AF XY: 0.00336 AC XY: 250 AN XY: 74442

African (AFR) AF: 0.00113 AC: 47 AN: 41570

American (AMR) AF: 0.00235 AC: 36 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00830 AC: 88 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00351 Hom.: 2

Bravo AF: 0.00303

EpiCase AF: 0.00431

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Atrial fibrillation, familial, 7 (3)
-	-	2	not provided (2)
-	-	1	KCNA5-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.4
DANN	Benign	0.83
PhyloP100		-0.54
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: rs12720444; hg19: chr12-5153883; COSMIC: COSV52904346;