2-226908750-T-C

Position:

• chr2-226908750-T-C

Variant summary

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

The NM_001167608.3(RHBDD1):​c.656-72T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,019,964 control chromosomes in the GnomAD database, including 92,446 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 0.44 (14575 hom., cov: 31)
  • Exomes 𝑓: 0.42 (77871 hom.)
• Consequence: RHBDD1 NM_001167608.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616

Genes affected

RHBDD1 (HGNC:23081): (rhomboid domain containing 1) Enables serine-type endopeptidase activity. Involved in several processes, including cellular response to unfolded protein; membrane protein proteolysis; and positive regulation of protein catabolic 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHBDD1	NM_001167608.3	c.656-72T>C		intron_variant		ENST00000392062.7	NP_001161080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHBDD1	ENST00000392062.7	c.656-72T>C		intron_variant		5	NM_001167608.3	ENSP00000375914	P1

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66072 AN: 151812 Hom.: 14548 Cov.: 31

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.419 AC: 363881 AN: 868032 Hom.: 77871 Cov.: 12 AF XY: 0.420 AC XY: 191811 AN XY: 456562

Gnomad4 AFR exome AF: 0.479

Gnomad4 AMR exome AF: 0.515

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.505

Gnomad4 FIN exome AF: 0.477

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.410

GnomAD4 genome AF: 0.435 AC: 66148 AN: 151932 Hom.: 14575 Cov.: 31 AF XY: 0.437 AC XY: 32487 AN XY: 74264

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.353

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.400

Gnomad4 OTH AF: 0.391

Alfa AF: 0.399 Hom.: 15329

Bravo AF: 0.436

Asia WGS AF: 0.442 AC: 1539 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.6
DANN	Benign	0.57

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: rs3820928; hg19: chr2-227773466; COSMIC: COSV58127174;