rs12626735

Variant names:

• chr21-33443672-G-C
• rs12626735
• ENST00000420455.5:n.*2037-4375C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000420455.5(TMEM50B):​n.*2037-4375C>G variant causes a intron 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.686
• Publications: 5 publications found

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]

IFNGR2 Gene-Disease associations (from GenCC):

• immunodeficiency 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TMEM50B	NR_040016.2	n.2692-4375C>G		intron_variant	Intron 7 of 8
TMEM50B	XM_011529746.3	c.*2037-4375C>G		intron_variant	Intron 7 of 9		XP_011528048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM50B	ENST00000420455.5	n.*2037-4375C>G		intron_variant	Intron 7 of 8	1		ENSP00000397773.1
IFNGR2	ENST00000421802.1	c.174+10801G>C		intron_variant	Intron 2 of 2	3		ENSP00000402629.1
TMEM50B	ENST00000468874.2	n.531+3346C>G		intron_variant	Intron 2 of 3	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

African (AFR) AF: 0.0495 AC: 2057 AN: 41534

American (AMR) AF: 0.234 AC: 3579 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 685 AN: 3468

East Asian (EAS) AF: 0.158 AC: 819 AN: 5182

South Asian (SAS) AF: 0.200 AC: 965 AN: 4820

European-Finnish (FIN) AF: 0.285 AC: 3005 AN: 10534

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16407 AN: 67982

Other (OTH) AF: 0.216 AC: 456 AN: 2112

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
PhyloP100		-0.69

Splicing

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

Other links and lift over

dbSNP: rs12626735; hg19: chr21-34815979;