2-231208212-T-G

Variant names:

• chr2-231208212-T-G
• rs1366767809
• NM_001352754.2:c.137T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001352754.2(ARMC9):​c.137T>G​(p.Val46Gly) 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. 15/21 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: ARMC9 NM_001352754.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.632

Genes affected

ARMC9 (HGNC:20730): (armadillo repeat containing 9) Predicted to be involved in cilium assembly and positive regulation of smoothened signaling pathway. Located in centriole and ciliary basal body. Implicated in Joubert syndrome 30. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04809335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMC9	NM_001352754.2	c.137T>G	p.Val46Gly	missense_variant	Exon 3 of 25	ENST00000611582.5	NP_001339683.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMC9	ENST00000611582.5	c.137T>G	p.Val46Gly	missense_variant	Exon 3 of 25	5	NM_001352754.2	ENSP00000484804.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces valine with glycine at codon 46 of the ARMC9 protein (p.Val46Gly). The valine residue is weakly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ARMC9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1473481). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.089	.;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.44	T;T;T;.
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.048	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L;.;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;.;N;.
REVEL	Benign	0.047
Sift	Benign	0.27	T;.;T;.
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0	.;B;.;B
Vest4		0.10
MutPred		0.36		Loss of stability (P = 0.0059);Loss of stability (P = 0.0059);Loss of stability (P = 0.0059);Loss of stability (P = 0.0059);
MVP		0.13
MPC		0.29
ClinPred		0.061	T
GERP RS		1.4
Varity_R		0.041
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1366767809; hg19: chr2-232072925;