20-63247738-C-T

Variant names:

• chr20-63247738-C-T
• rs927666296
• NM_152864.4:c.311G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152864.4(NKAIN4):​c.311G>A​(p.Arg104His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,486,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NKAIN4 NM_152864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.763
• Publications: 0 publications found

Genes affected

NKAIN4 (HGNC:16191): (sodium/potassium transporting ATPase interacting 4) NKAIN4 is a member of a family of mammalian proteins (see NKAIN1; MIM 612871) with similarity to Drosophila Nkain and interacts with the beta subunit of Na,K-ATPase (ATP1B1; MIM 182330) (Gorokhova et al., 2007 [PubMed 17606467]).[supplied by OMIM, Jun 2009]

LOC124904950 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.269584).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152864.4. 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
	NKAIN4	NM_152864.4	MANE Select	c.311G>A	p.Arg104His	missense	Exon 4 of 7	NP_690603.3
	NKAIN4	NM_001363747.1		c.125G>A	p.Arg42His	missense	Exon 4 of 7	NP_001350676.1	A6NNM2
	NKAIN4	NM_001363718.1		c.125G>A	p.Arg42His	missense	Exon 4 of 6	NP_001350647.1	J3JS66

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKAIN4	ENST00000370316.8	TSL:1 MANE Select	c.311G>A	p.Arg104His	missense	Exon 4 of 7	ENSP00000359340.3	Q8IVV8
	NKAIN4	ENST00000370317.3	TSL:5	c.101G>A	p.Arg34His	missense	Exon 2 of 6	ENSP00000359341.3	J9JIE8
	NKAIN4	ENST00000370307.6	TSL:5	c.125G>A	p.Arg42His	missense	Exon 4 of 7	ENSP00000359330.2	A6NNM2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 15 AN: 1334586 Hom.: 0 Cov.: 34 AF XY: 0.0000123 AC XY: 8 AN XY: 650622

African (AFR) AF: 0.00 AC: 0 AN: 29702

American (AMR) AF: 0.00 AC: 0 AN: 27234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21452

East Asian (EAS) AF: 0.00 AC: 0 AN: 34956

South Asian (SAS) AF: 0.0000146 AC: 1 AN: 68392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5294

European-Non Finnish (NFE) AF: 0.0000134 AC: 14 AN: 1046296

Other (OTH) AF: 0.00 AC: 0 AN: 55188

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74364

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

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.76
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.047
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.077	B
Vest4		0.10
MutPred		0.77		Loss of MoRF binding (P = 0.0178)
MVP		0.048
MPC		0.0095
ClinPred		0.14	T
GERP RS		-2.0
Varity_R		0.081
gMVP		0.13
Mutation Taster		=83/17	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: rs927666296; hg19: chr20-61879090;