2-231276776-G-C

Variant names:

• chr2-231276776-G-C
• rs1114167448
• NM_001352754.2:c.1474+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001352754.2(ARMC9):​c.1474+1G>C variant causes a splice donor, intron 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. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARMC9 NM_001352754.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 8.55
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-231276776-G-C is Pathogenic according to our data. Variant chr2-231276776-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 427934.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC9	NM_001352754.2	MANE Select	c.1474+1G>C		splice_donor intron	N/A	NP_001339683.2
	ARMC9	NM_001271466.4		c.1474+1G>C		splice_donor intron	N/A	NP_001258395.2
	ARMC9	NM_001291656.2		c.1474+1G>C		splice_donor intron	N/A	NP_001278585.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC9	ENST00000611582.5	TSL:5 MANE Select	c.1474+1G>C		splice_donor intron	N/A	ENSP00000484804.1
	ARMC9	ENST00000349938.8	TSL:1	c.1474+1G>C		splice_donor intron	N/A	ENSP00000258417.5
	ARMC9	ENST00000684224.1		n.1029G>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

ARMC9-related Joubert syndrome Pathogenic:1

May 01, 2017

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Joubert syndrome 30 Pathogenic:1

Aug 16, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Joubert syndrome Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.5
GERP RS		5.3
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

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

Other links and lift over

dbSNP: rs1114167448; hg19: chr2-232141489;