2-216100400-G-C

Position:

• chr2-216100400-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142311.2(TMEM169):​c.752G>C​(p.Gly251Ala) variant causes a missense change involving the alteration of a 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM169 NM_001142311.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.75

Genes affected

TMEM169 (HGNC:25130): (transmembrane protein 169) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM169	NM_001142311.2	c.752G>C	p.Gly251Ala	missense_variant	3/3	ENST00000437356.7	NP_001135783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM169	ENST00000437356.7	c.752G>C	p.Gly251Ala	missense_variant	3/3	1	NM_001142311.2	ENSP00000401305	P1
TMEM169	ENST00000406027.2	c.752G>C	p.Gly251Ala	missense_variant	3/3	1		ENSP00000384100	P1
TMEM169	ENST00000295658.8	c.752G>C	p.Gly251Ala	missense_variant	3/3	2		ENSP00000295658	P1
TMEM169	ENST00000454545.5	c.752G>C	p.Gly251Ala	missense_variant	4/4	4		ENSP00000412524	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.752G>C (p.G251A) alteration is located in exon 4 (coding exon 2) of the TMEM169 gene. This alteration results from a G to C substitution at nucleotide position 752, causing the glycine (G) at amino acid position 251 to be replaced by an alanine (A). 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	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;.;.;.
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.8	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.93
MutPred		0.69		Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);
MVP		0.35
MPC		0.60
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.89

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: rs1559230462; hg19: chr2-216965123;