chr1-205241893-G-T

Variant names:

• chr1-205241893-G-T
• rs375718104
• NM_014858.4:c.596G>T

Variant summary

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

The NM_014858.4(TMCC2):​c.596G>T​(p.Arg199Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,284 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. R199H) 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: 6.25
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMCC2	NM_014858.4	c.596G>T	p.Arg199Leu	missense_variant	Exon 2 of 5	ENST00000358024.8	NP_055673.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCC2	ENST00000358024.8	c.596G>T	p.Arg199Leu	missense_variant	Exon 2 of 5	1	NM_014858.4	ENSP00000350718.3
TMCC2	ENST00000545499.5	c.362G>T	p.Arg121Leu	missense_variant	Exon 2 of 5	2		ENSP00000437943.1
TMCC2	ENST00000495538.5	n.827G>T		non_coding_transcript_exon_variant	Exon 2 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455284 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723770

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5154

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110534

Other (OTH) AF: 0.00 AC: 0 AN: 60036

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	-0.046
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		6.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.081	T;T
Polyphen		0.0	B;.
Vest4		0.67
MutPred		0.40		Loss of MoRF binding (P = 0.0214);.;
MVP		0.62
MPC		0.82
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.16
gMVP		0.67
Mutation Taster		=84/16	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: rs375718104; hg19: chr1-205211021;