18-79919345-G-C

Variant names:

• chr18-79919345-G-C
• rs373259554
• NM_025078.5:c.447C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025078.5(SLC66A2):​c.447C>G​(p.Cys149Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C149C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC66A2 NM_025078.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240
• Publications: 0 publications found

Genes affected

SLC66A2 (HGNC:26188): (solute carrier family 66 member 2) Predicted to be involved in phospholipid translocation and retrograde transport, endosome to Golgi. Predicted to be located in cytosol. Predicted to be integral component of membrane. Predicted to be active in endosome and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025078.5. 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
	SLC66A2	NM_025078.5	MANE Select	c.447C>G	p.Cys149Trp	missense	Exon 5 of 6	NP_079354.2
	SLC66A2	NM_001146345.2		c.393C>G	p.Cys131Trp	missense	Exon 4 of 5	NP_001139817.1	Q8N2U9-2
	SLC66A2	NM_001146343.2		c.338-15162C>G		intron	N/A	NP_001139815.1	Q8N2U9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC66A2	ENST00000397778.7	TSL:1 MANE Select	c.447C>G	p.Cys149Trp	missense	Exon 5 of 6	ENSP00000380880.2	Q8N2U9-1
	SLC66A2	ENST00000954269.1		c.642C>G	p.Cys214Trp	missense	Exon 7 of 8	ENSP00000624328.1
	SLC66A2	ENST00000954270.1		c.639C>G	p.Cys213Trp	missense	Exon 7 of 8	ENSP00000624329.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250238 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000619

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460914 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726762

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74396

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

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: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.0025
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		-0.024
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.63		Gain of helix (P = 0.0854)
MVP		0.14
MPC		0.85
ClinPred		0.69	D
GERP RS		-1.2
Varity_R		0.28
gMVP		0.85
Mutation Taster		=26/74	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: rs373259554; hg19: chr18-77679345;