22-17119935-C-T

Variant names:

• chr22-17119935-C-T
• rs1040909265
• NM_031890.4:c.1193G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031890.4(TMEM121B):​c.1193G>A​(p.Gly398Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM121B NM_031890.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.315

Genes affected

TMEM121B (HGNC:1844): (transmembrane protein 121B)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24747226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM121B	NM_031890.4	c.1193G>A	p.Gly398Asp	missense_variant	Exon 1 of 1	ENST00000331437.4	NP_114096.1
TMEM121B	NM_001163079.2	c.128G>A	p.Gly43Asp	missense_variant	Exon 2 of 2		NP_001156551.1
TMEM121B	XM_011546124.3	c.1193G>A	p.Gly398Asp	missense_variant	Exon 1 of 2		XP_011544426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM121B	ENST00000331437.4	c.1193G>A	p.Gly398Asp	missense_variant	Exon 1 of 1	6	NM_031890.4	ENSP00000329318.3
TMEM121B	ENST00000399875.1	c.128G>A	p.Gly43Asp	missense_variant	Exon 2 of 2	2		ENSP00000382764.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419512 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 704076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000260

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1193G>A (p.G398D) alteration is located in exon 1 (coding exon 1) of the CECR6 gene. This alteration results from a G to A substitution at nucleotide position 1193, causing the glycine (G) at amino acid position 398 to be replaced by an aspartic acid (D). 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	0.94
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.3	D;N
REVEL	Uncertain	0.46
Sift	Benign	0.038	D;D
Sift4G	Benign	0.075	T;D
Polyphen		0.85	.;P
Vest4		0.38
MutPred		0.33		.;Loss of catalytic residue at C400 (P = 0.0544);
MVP		0.35
ClinPred		0.97	D
GERP RS		1.8
Varity_R		0.34
gMVP		0.76

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: rs1040909265; hg19: chr22-17600825;