5-170378407-T-G

Variant names:

• chr5-170378407-T-G
• rs314156
• NM_004137.4:c.*297A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004137.4(KCNMB1):​c.*297A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000545 in 183,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KCNMB1 NM_004137.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 0 publications found

Genes affected

KCNMB1 (HGNC:6285): (potassium calcium-activated channel subfamily M regulatory beta subunit 1) MaxiK channels are large conductance, voltage and calcium-sensitive potassium channels which are fundamental to the control of smooth muscle tone and neuronal excitability. MaxiK channels can be formed by 2 subunits: the pore-forming alpha subunit and the product of this gene, the modulatory beta subunit. Intracellular calcium regulates the physical association between the alpha and beta subunits. [provided by RefSeq, Jul 2008]

KCNIP1 (HGNC:15521): (potassium voltage-gated channel interacting protein 1) This gene encodes a member of the family of cytosolic voltage-gated potassium (Kv) channel-interacting proteins (KCNIPs), which belong to the neuronal calcium sensor (NCS) family of the calcium binding EF-hand proteins. They associate with Kv4 alpha subunits to form native Kv4 channel complexes. The encoded protein may regulate rapidly inactivating (A-type) currents, and hence neuronal membrane excitability, in response to changes in the concentration of intracellular calcium. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMB1	NM_004137.4	c.*297A>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000274629.9	NP_004128.1
KCNIP1	NM_001034838.3	c.88+24443T>G		intron_variant	Intron 1 of 7		NP_001030010.1
KCNIP1	XM_017009407.2	c.88+24443T>G		intron_variant	Intron 2 of 8		XP_016864896.1
KCNIP1	XM_017009408.2	c.88+24443T>G		intron_variant	Intron 1 of 3		XP_016864897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMB1	ENST00000274629.9	c.*297A>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_004137.4	ENSP00000274629.3
KCNIP1	ENST00000377360.8	c.88+24443T>G		intron_variant	Intron 1 of 7	1		ENSP00000366577.4
KCNIP1	ENST00000517344.1	n.88+24443T>G		intron_variant	Intron 1 of 3	3		ENSP00000431053.1
KCNIP1	ENST00000518527.1	n.478+24443T>G		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000545 AC: 1 AN: 183394 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 92778

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 5722

American (AMR) AF: 0.00 AC: 0 AN: 6896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6566

East Asian (EAS) AF: 0.00 AC: 0 AN: 13874

South Asian (SAS) AF: 0.00 AC: 0 AN: 9114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 958

European-Non Finnish (NFE) AF: 0.00000850 AC: 1 AN: 117606

Other (OTH) AF: 0.00 AC: 0 AN: 12062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.24
DANN	Benign	0.60
PhyloP100		-1.7

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: rs314156; hg19: chr5-169805411;