chr15-72398795-C-G

Position:

• chr15-72398795-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080462.3(TMEM202):​c.224C>G​(p.Ser75Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TMEM202 NM_001080462.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.889

Genes affected

TMEM202 (HGNC:33733): (transmembrane protein 202) Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3601706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM202	NM_001080462.3	c.224C>G	p.Ser75Cys	missense_variant	2/5	ENST00000341689.4	NP_001073931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM202	ENST00000341689.4	c.224C>G	p.Ser75Cys	missense_variant	2/5	5	NM_001080462.3	ENSP00000340212	P1
TMEM202	ENST00000567679.1	c.81+388C>G		intron_variant		2		ENSP00000456083
TMEM202	ENST00000649825.1	c.-67+388C>G		intron_variant				ENSP00000497819
TMEM202	ENST00000568167.5	c.81+388C>G		intron_variant, NMD_transcript_variant		2		ENSP00000457632

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2024

The c.224C>G (p.S75C) alteration is located in exon 2 (coding exon 2) of the TMEM202 gene. This alteration results from a C to G substitution at nucleotide position 224, causing the serine (S) at amino acid position 75 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.50	D;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.75	P
Vest4		0.50
MutPred		0.40		Gain of helix (P = 0.062);
MVP		0.26
MPC		0.46
ClinPred		0.96	D
GERP RS		2.5
Varity_R		0.32
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs1040475769; hg19: chr15-72691136;