22-17119894-G-C

Position:

• chr22-17119894-G-C

Variant summary

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

The NM_031890.4(TMEM121B):​c.1234C>G​(p.Leu412Val) 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 benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM121B NM_031890.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.326

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=0.11002195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM121B	NM_031890.4	c.1234C>G	p.Leu412Val	missense_variant	1/1	ENST00000331437.4	NP_114096.1
TMEM121B	NM_001163079.2	c.169C>G	p.Leu57Val	missense_variant	2/2		NP_001156551.1
TMEM121B	XM_011546124.3	c.1234C>G	p.Leu412Val	missense_variant	1/2		XP_011544426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM121B	ENST00000331437.4	c.1234C>G	p.Leu412Val	missense_variant	1/1		NM_031890.4	ENSP00000329318	P1
TMEM121B	ENST00000399875.1	c.169C>G	p.Leu57Val	missense_variant	2/2	2		ENSP00000382764

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

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

Jun 22, 2023

The c.1234C>G (p.L412V) alteration is located in exon 1 (coding exon 1) of the CECR6 gene. This alteration results from a C to G substitution at nucleotide position 1234, causing the leucine (L) at amino acid position 412 to be replaced by a valine (V). 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	Benign	0.23
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.70	D;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.055
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.018	D;T
Polyphen		0.71	.;P
Vest4		0.086
MutPred		0.28		.;Loss of stability (P = 0.0557);
MVP		0.22
ClinPred		0.70	D
GERP RS		3.3
Varity_R		0.16
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-17600784;