2-231208199-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001352754.2(ARMC9):c.124T>C(p.Leu42=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,607,608 control chromosomes in the GnomAD database, including 52,228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6433 hom., cov: 33)
  • Exomes 𝑓: 0.25 (45795 hom.)
• Consequence: ARMC9 NM_001352754.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0180

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-231208199-T-C is Benign according to our data. Variant chr2-231208199-T-C is described in ClinVar as [Benign]. Clinvar id is 1167998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.018 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMC9	NM_001352754.2	c.124T>C	p.Leu42=	synonymous_variant	3/25	ENST00000611582.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMC9	ENST00000611582.5	c.124T>C	p.Leu42=	synonymous_variant	3/25	5	NM_001352754.2	P1

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43202 AN: 152006 Hom.: 6427 Cov.: 33

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.292

GnomAD3 exomes AF: 0.255 AC: 63014 AN: 247226 Hom.: 8652 AF XY: 0.251 AC XY: 33592 AN XY: 133648

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.318

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.247 AC: 359555 AN: 1455484 Hom.: 45795 Cov.: 31 AF XY: 0.245 AC XY: 177278 AN XY: 724002

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.284 AC: 43242 AN: 152124 Hom.: 6433 Cov.: 33 AF XY: 0.284 AC XY: 21148 AN XY: 74356

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.289

Alfa AF: 0.273 Hom.: 2977

Bravo AF: 0.282

Asia WGS AF: 0.194 AC: 676 AN: 3478

EpiCase AF: 0.254

EpiControl AF: 0.257

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.4
Dann	Benign	0.71

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: rs11558174; hg19: chr2-232072912; COSMIC: COSV63019960;