1-205241790-G-C

Variant names:

• chr1-205241790-G-C
• rs201022917
• NM_014858.4:c.493G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014858.4(TMCC2):​c.493G>C​(p.Ala165Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. A165T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMCC2 NM_014858.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08591309).

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.493G>C	p.Ala165Pro	missense	Exon 2 of 5	NP_055673.2	O75069-1
	TMCC2	NM_001242925.2		c.259G>C	p.Ala87Pro	missense	Exon 2 of 5	NP_001229854.1	O75069-2
	TMCC2	NM_001375651.1		c.259G>C	p.Ala87Pro	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.493G>C	p.Ala165Pro	missense	Exon 2 of 5	ENSP00000350718.3	O75069-1
	TMCC2	ENST00000962349.1		c.493G>C	p.Ala165Pro	missense	Exon 3 of 6	ENSP00000632408.1
	TMCC2	ENST00000545499.5	TSL:2	c.259G>C	p.Ala87Pro	missense	Exon 2 of 5	ENSP00000437943.1	O75069-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00124 AC: 268 AN: 216552 AF XY: 0.00113

Gnomad AFR exome AF: 0.00506

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.000324

Gnomad EAS exome AF: 0.00227

Gnomad FIN exome AF: 0.00101

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.000554

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000111 AC: 161 AN: 1448198 Hom.: 0 Cov.: 31 AF XY: 0.000132 AC XY: 95 AN XY: 719992

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

African (AFR) AF: 0.000121 AC: 4 AN: 33038

American (AMR) AF: 0.000798 AC: 34 AN: 42588

Ashkenazi Jewish (ASJ) AF: 0.0000774 AC: 2 AN: 25838

East Asian (EAS) AF: 0.000673 AC: 26 AN: 38606

South Asian (SAS) AF: 0.0000470 AC: 4 AN: 85150

European-Finnish (FIN) AF: 0.00122 AC: 60 AN: 49358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.0000226 AC: 25 AN: 1108184

Other (OTH) AF: 0.000100 AC: 6 AN: 59812

⚠️ 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

Alfa AF: 0.000174 Hom.: 0

ExAC AF: 0.000543 AC: 64

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.096
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.035	D
Polyphen		0.80	P
Vest4		0.22
MVP		0.56
MPC		1.3
ClinPred		0.028	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.50
Mutation Taster		=85/15	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: rs201022917; hg19: chr1-205210918;