rs1172147

Positions:

• chr1-205256329-G-A
• chr1-205256329-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014858.4(TMCC2):​c.748-12621G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,550,110 control chromosomes in the GnomAD database, including 103,381 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (7514 hom., cov: 33)
  • Exomes 𝑓: 0.36 (95867 hom.)
• Consequence: TMCC2 NM_014858.4 intron
• Scores: Splicing: ADA: 0.00006354
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCC2	NM_014858.4	c.748-12621G>A		intron_variant		ENST00000358024.8	NP_055673.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMCC2	ENST00000358024.8	c.748-12621G>A		intron_variant		1	NM_014858.4	ENSP00000350718	P3

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43976 AN: 152092 Hom.: 7516 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.0534

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.305

GnomAD3 exomes AF: 0.283 AC: 42485 AN: 149896 Hom.: 7326 AF XY: 0.279 AC XY: 22464 AN XY: 80580

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.0499

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.328

GnomAD4 exome AF: 0.358 AC: 500006 AN: 1397900 Hom.: 95867 Cov.: 39 AF XY: 0.351 AC XY: 242282 AN XY: 689512

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.0637

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.408

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.316

GnomAD4 genome AF: 0.289 AC: 43984 AN: 152210 Hom.: 7514 Cov.: 33 AF XY: 0.285 AC XY: 21173 AN XY: 74414

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.0535

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.425

Gnomad4 NFE AF: 0.389

Gnomad4 OTH AF: 0.303

Alfa AF: 0.368 Hom.: 20944

Bravo AF: 0.272

Asia WGS AF: 0.0860 AC: 305 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.66
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs1172147; hg19: chr1-205225457; COSMIC: COSV58003392; COSMIC: COSV58003392;