6-108868953-C-T

Variant names:

• chr6-108868953-C-T
• rs1562332833
• NM_032131.6:c.421C>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_032131.6(ARMC2):​c.421C>T​(p.Gln141*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARMC2 NM_032131.6 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.54

Genes affected

ARMC2 (HGNC:23045): (armadillo repeat containing 2) Involved in sperm axoneme assembly. Implicated in spermatogenic failure 38. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-108868953-C-T is Pathogenic according to our data. Variant chr6-108868953-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 627631.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-108868953-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMC2	NM_032131.6	c.421C>T	p.Gln141*	stop_gained	Exon 4 of 18	ENST00000392644.9	NP_115507.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMC2	ENST00000392644.9	c.421C>T	p.Gln141*	stop_gained	Exon 4 of 18	1	NM_032131.6	ENSP00000376417.4
ARMC2	ENST00000237512.4	c.421C>T	p.Gln141*	stop_gained	Exon 4 of 5	2		ENSP00000237512.4
ARMC2	ENST00000368972	c.-75C>T		5_prime_UTR_variant	Exon 3 of 17	2		ENSP00000357968.3
ARMC2	ENST00000414610.1	c.-27C>T		upstream_gene_variant		5		ENSP00000393191.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 38 Pathogenic:1

May 15, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Male infertility with teratozoospermia due to single gene mutation Pathogenic:1

Dec 17, 2018

Genetics of Infertility and Preimplantation Genetic Diagnosis, Centre Hospitalier Universitaire Grenoble Alpes

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Benign	0.75	D
Vest4		0.17
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1562332833; hg19: chr6-109190156;