2-231208212-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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
• Publications: 0 publications found

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]

ARMC9 Gene-Disease associations (from GenCC):

• Joubert syndrome 30

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352754.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC9	NM_001352754.2	MANE Select	c.137T>G	p.Val46Gly	missense	Exon 3 of 25	NP_001339683.2	Q7Z3E5-1
	ARMC9	NM_001271466.4		c.137T>G	p.Val46Gly	missense	Exon 3 of 25	NP_001258395.2	Q7Z3E5-1
	ARMC9	NM_001291656.2		c.137T>G	p.Val46Gly	missense	Exon 3 of 21	NP_001278585.2	A0A2Q3DP09

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC9	ENST00000611582.5	TSL:5 MANE Select	c.137T>G	p.Val46Gly	missense	Exon 3 of 25	ENSP00000484804.1	Q7Z3E5-1
	ARMC9	ENST00000349938.8	TSL:1	c.137T>G	p.Val46Gly	missense	Exon 3 of 21	ENSP00000258417.5	A0A2Q3DP09
	ARMC9	ENST00000958134.1		c.137T>G	p.Val46Gly	missense	Exon 3 of 26	ENSP00000628193.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.63
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.047
Sift	Benign	0.27	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.36		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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1366767809; hg19: chr2-232072925;