rs12626735

chr21-33443672-G-CchrNW_003315970.2-38243-G-C

Variant summary

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

The ENST00000420455.5(TMEM50B):c.*2037-4375C>G variant causes a intron, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,106 control chromosomes in the GnomAD database, including 3,210 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 0.19 (3210 hom., cov: 33)
• Consequence: TMEM50B ENST00000420455.5 intron, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.686

Genes affected

TMEM50B (HGNC:1280): (transmembrane protein 50B) Predicted to be involved in late endosome to vacuole transport via multivesicular body sorting pathway. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

IFNGR2 (HGNC:5440): (interferon gamma receptor 2) This gene (IFNGR2) encodes the non-ligand-binding beta chain of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. Defects in IFNGR2 are a cause of mendelian susceptibility to mycobacterial disease (MSMD), also known as familial disseminated atypical mycobacterial infection. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM50B	XM_011529746.3	c.*2037-4375C>G		intron_variant
TMEM50B	NR_040016.2	n.2692-4375C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM50B	ENST00000420455.5	c.*2037-4375C>G		intron_variant, NMD_transcript_variant		1
IFNGR2	ENST00000421802.1	c.176+10801G>C		intron_variant		3
TMEM50B	ENST00000468874.2	n.531+3346C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28262 AN: 151990 Hom.: 3206 Cov.: 33

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.216

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.186 AC: 28278 AN: 152106 Hom.: 3210 Cov.: 33 AF XY: 0.191 AC XY: 14179 AN XY: 74338

Gnomad4 AFR AF: 0.0495

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.216

Alfa AF: 0.211 Hom.: 461

Bravo AF: 0.176

Asia WGS AF: 0.188 AC: 656 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.49
Dann	Benign	0.48

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12626735; hg19: chr21-34815979;