chr12-10186478-C-A

Variant names:

• chr12-10186478-C-A
• rs755716852
• NM_001384896.1:c.196C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001384896.1(TMEM52B):​c.196C>A​(p.Arg66Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,300 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R66H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM52B NM_001384896.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.44
• Publications: 0 publications found

Genes affected

TMEM52B (HGNC:26438): (transmembrane protein 52B) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384896.1. 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
	TMEM52B	NM_001384896.1	MANE Select	c.196C>A	p.Arg66Ser	missense	Exon 4 of 5	NP_001371825.1	Q4KMG9-1
	TMEM52B	NM_001079815.2		c.196C>A	p.Arg66Ser	missense	Exon 5 of 6	NP_001073283.1	Q4KMG9-1
	TMEM52B	NM_001384894.1		c.196C>A	p.Arg66Ser	missense	Exon 7 of 8	NP_001371823.1	Q4KMG9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM52B	ENST00000543484.2	TSL:4 MANE Select	c.196C>A	p.Arg66Ser	missense	Exon 4 of 5	ENSP00000445582.2	Q4KMG9-1
	TMEM52B	ENST00000298530.7	TSL:1	c.136C>A	p.Arg46Ser	missense	Exon 3 of 4	ENSP00000298530.3	Q4KMG9-2
	TMEM52B	ENST00000381923.6	TSL:5	c.196C>A	p.Arg66Ser	missense	Exon 5 of 6	ENSP00000371348.2	Q4KMG9-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460300 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726492

African (AFR) AF: 0.00 AC: 0 AN: 33474

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110752

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.4
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.60		Gain of catalytic residue at S62 (P = 0)
MVP		0.50
MPC		0.48
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.51
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755716852; hg19: chr12-10339077;