1-61725045-C-G

Variant names:

• chr1-61725045-C-G
• rs200877661
• NM_032027.3:c.76G>C

Variant summary

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

The NM_032027.3(TM2D1):​c.76G>C​(p.Val26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TM2D1 NM_032027.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190

Genes affected

TM2D1 (HGNC:24142): (TM2 domain containing 1) The protein encoded by this gene is a beta-amyloid peptide-binding protein. It contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily and known to be important in heterotrimeric G protein activation. Beta-amyloid peptide has been established to be a causative factor in neuron death and the consequent diminution of cognitive abilities observed in Alzheimer's disease. This protein may be a target of neurotoxic beta-amyloid peptide, and may mediate cellular vulnerability to beta-amyloid peptide toxicity through a G protein-regulated program of cell death. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

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=0.012125462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM2D1	NM_032027.3	c.76G>C	p.Val26Leu	missense_variant	Exon 1 of 7	ENST00000606498.5	NP_114416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM2D1	ENST00000606498.5	c.76G>C	p.Val26Leu	missense_variant	Exon 1 of 7	5	NM_032027.3	ENSP00000475700.1
TM2D1	ENST00000371180.7	c.76G>C	p.Val26Leu	missense_variant	Exon 1 of 7	5		ENSP00000360222.2
TM2D1	ENST00000371177.2	c.76G>C	p.Val26Leu	missense_variant	Exon 1 of 5	5		ENSP00000475297.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000178 AC: 44 AN: 247136 Hom.: 0 AF XY: 0.000186 AC XY: 25 AN XY: 134360

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 105 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74366

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000244 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76G>C (p.V26L) alteration is located in exon 1 (coding exon 1) of the TM2D1 gene. This alteration results from a G to C substitution at nucleotide position 76, causing the valine (V) at amino acid position 26 to be replaced by a leucine (L). 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	0.078
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0089	T;T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.76	.;T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.11	.;N;N;.
REVEL	Benign	0.032
Sift	Benign	0.34	.;T;T;.
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.22
MVP		0.17
MPC		0.26
ClinPred		0.065	T
GERP RS		2.7
Varity_R		0.043
gMVP		0.49

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: rs200877661; hg19: chr1-62190717;