NM_001101312.2:c.223G>C

Variant names:

• chr7-150794053-C-G
• NM_001101312.2:c.223G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001101312.2(TMEM176B):​c.223G>C​(p.Gly75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G75E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMEM176B NM_001101312.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

Genes affected

TMEM176B (HGNC:29596): (transmembrane protein 176B) Predicted to be involved in negative regulation of dendritic cell differentiation. Predicted to be located in nuclear membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM176B	NM_001101312.2	c.223G>C	p.Gly75Arg	missense_variant	Exon 3 of 7	ENST00000326442.10	NP_001094782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM176B	ENST00000326442.10	c.223G>C	p.Gly75Arg	missense_variant	Exon 3 of 7	1	NM_001101312.2	ENSP00000318409.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.223G>C (p.G75R) alteration is located in exon 3 (coding exon 2) of the TMEM176B gene. This alteration results from a G to C substitution at nucleotide position 223, causing the glycine (G) at amino acid position 75 to be replaced by an arginine (R). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	.;.;.;D;.
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M;M;M
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.9	D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.82
MutPred		0.87		Loss of catalytic residue at V76 (P = 0.0176);Loss of catalytic residue at V76 (P = 0.0176);Loss of catalytic residue at V76 (P = 0.0176);Loss of catalytic residue at V76 (P = 0.0176);Loss of catalytic residue at V76 (P = 0.0176);
MVP		0.48
MPC		0.31
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.81
gMVP		0.72
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

hg19: chr7-150491141;