1-205241785-G-T

Variant names:

• chr1-205241785-G-T
• rs1261820035
• NM_014858.4:c.488G>T

Variant summary

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

The NM_014858.4(TMCC2):​c.488G>T​(p.Arg163Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,234 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. R163Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMCC2 NM_014858.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.38
• Publications: 0 publications found

Genes affected

TMCC2 (HGNC:24239): (transmembrane and coiled-coil domain family 2) Involved in amyloid precursor protein metabolic process. Located in endoplasmic reticulum. [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, 0.757

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014858.4. 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
	TMCC2	NM_014858.4	MANE Select	c.488G>T	p.Arg163Leu	missense	Exon 2 of 5	NP_055673.2	O75069-1
	TMCC2	NM_001242925.2		c.254G>T	p.Arg85Leu	missense	Exon 2 of 5	NP_001229854.1	O75069-2
	TMCC2	NM_001375651.1		c.254G>T	p.Arg85Leu	missense	Exon 2 of 5	NP_001362580.1	O75069-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCC2	ENST00000358024.8	TSL:1 MANE Select	c.488G>T	p.Arg163Leu	missense	Exon 2 of 5	ENSP00000350718.3	O75069-1
	TMCC2	ENST00000962349.1		c.488G>T	p.Arg163Leu	missense	Exon 3 of 6	ENSP00000632408.1
	TMCC2	ENST00000545499.5	TSL:2	c.254G>T	p.Arg85Leu	missense	Exon 2 of 5	ENSP00000437943.1	O75069-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456234 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724318

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110596

Other (OTH) AF: 0.00 AC: 0 AN: 60070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.072	T
Polyphen		0.99	D
Vest4		0.89
MutPred		0.44		Loss of methylation at R163 (P = 0.0251)
MVP		0.71
MPC		1.5
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.41
gMVP		0.68
Mutation Taster		=75/25	polymorphism

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: rs1261820035; hg19: chr1-205210913;