NM_017964.5:c.762A>C

Variant names:

• chr2-32204686-A-C
• rs376875798
• NM_017964.5:c.762A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017964.5(SLC30A6):​c.762A>C​(p.Leu254Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000388 in 1,596,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SLC30A6 NM_017964.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.150
• Publications: 1 publications found

Genes affected

SLC30A6 (HGNC:19305): (solute carrier family 30 member 6) This gene encodes a member of a family of proteins that function as zinc transporters. This protein can regulate subcellular levels of zinc in the Golgi and vesicles. Expression of this gene is altered in the Alzheimer's disease brain plaques. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017964.5. 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
	SLC30A6	NM_017964.5	MANE Select	c.762A>C	p.Leu254Phe	missense	Exon 11 of 14	NP_060434.2
	SLC30A6	NM_001193513.3		c.882A>C	p.Leu294Phe	missense	Exon 12 of 15	NP_001180442.1	Q6NXT4-2
	SLC30A6	NM_001193514.3		c.762A>C	p.Leu254Phe	missense	Exon 11 of 13	NP_001180443.1	Q6NXT4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC30A6	ENST00000282587.9	TSL:1 MANE Select	c.762A>C	p.Leu254Phe	missense	Exon 11 of 14	ENSP00000282587.5	Q6NXT4-1
	SLC30A6	ENST00000379343.6	TSL:1	c.882A>C	p.Leu294Phe	missense	Exon 12 of 15	ENSP00000368648.2	Q6NXT4-2
	SLC30A6	ENST00000435660.5	TSL:1	c.762A>C	p.Leu254Phe	missense	Exon 11 of 13	ENSP00000399005.1	Q6NXT4-3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151830 Hom.: 0 Cov.: 32

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251000 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000401 AC: 58 AN: 1444908 Hom.: 0 Cov.: 28 AF XY: 0.0000459 AC XY: 33 AN XY: 718802

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25576

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39528

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000509 AC: 56 AN: 1100578

Other (OTH) AF: 0.00 AC: 0 AN: 59490

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151830 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74126

African (AFR) AF: 0.00 AC: 0 AN: 41322

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.11
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.65	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.0096	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.15
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.84		Gain of catalytic residue at L254 (P = 0.0352)
MVP		0.72
MPC		0.23
ClinPred		0.96	D
GERP RS		-0.86
Varity_R		0.29
gMVP		0.91
Mutation Taster		=34/66	disease causing

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: rs376875798; hg19: chr2-32429755;