18-79919395-C-G

Variant names:

• chr18-79919395-C-G
• rs748167009
• NM_025078.5:c.397G>C

Variant summary

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

The NM_025078.5(SLC66A2):​c.397G>C​(p.Asp133His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,342 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D133N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC66A2 NM_025078.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.76
• 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, 0.783

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.397G>C	p.Asp133His	missense	Exon 5 of 6	NP_079354.2
	SLC66A2	NM_001146345.2		c.343G>C	p.Asp115His	missense	Exon 4 of 5	NP_001139817.1	Q8N2U9-2
	SLC66A2	NM_001146343.2		c.338-15212G>C		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.397G>C	p.Asp133His	missense	Exon 5 of 6	ENSP00000380880.2	Q8N2U9-1
	SLC66A2	ENST00000954269.1		c.592G>C	p.Asp198His	missense	Exon 7 of 8	ENSP00000624328.1
	SLC66A2	ENST00000954270.1		c.589G>C	p.Asp197His	missense	Exon 7 of 8	ENSP00000624329.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460342 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726454

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111750

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.61		Gain of helix (P = 0.0496)
MVP		0.081
MPC		0.75
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.73
gMVP		0.73
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748167009; hg19: chr18-77679395;