chr1-205241638-T-C

Position:

• chr1-205241638-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014858.4(TMCC2):​c.341T>C​(p.Met114Thr) 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. 14/21 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)
• Consequence: TMCC2 NM_014858.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062354982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMCC2	NM_014858.4	c.341T>C	p.Met114Thr	missense_variant	2/5	ENST00000358024.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCC2	ENST00000358024.8	c.341T>C	p.Met114Thr	missense_variant	2/5	1	NM_014858.4	P3
TMCC2	ENST00000545499.5	c.107T>C	p.Met36Thr	missense_variant	2/5	2		A1
TMCC2	ENST00000495538.5	n.572T>C		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 26, 2022

The c.341T>C (p.M114T) alteration is located in exon 2 (coding exon 2) of the TMCC2 gene. This alteration results from a T to C substitution at nucleotide position 341, causing the methionine (M) at amino acid position 114 to be replaced by a threonine (T). 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	0.097
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.098
Sift	Benign	0.18	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0	B;.
Vest4		0.18
MutPred		0.12		Gain of phosphorylation at M114 (P = 0.012);.;
MVP		0.26
MPC		0.67
ClinPred		0.054	T
GERP RS		3.6
Varity_R		0.056
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-205210766;