6-108868852-G-A

Variant summary

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

The NM_032131.6(ARMC2):c.320G>A(p.Arg107Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARMC2 NM_032131.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0720

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 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=0.025710583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMC2	NM_032131.6	c.320G>A	p.Arg107Lys	missense_variant	4/18	ENST00000392644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMC2	ENST00000392644.9	c.320G>A	p.Arg107Lys	missense_variant	4/18	1	NM_032131.6	P1
ARMC2	ENST00000237512.4	c.320G>A	p.Arg107Lys	missense_variant	4/5	2
ARMC2	ENST00000368972.7	c.-176G>A		5_prime_UTR_variant	3/17	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461346 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.320G>A (p.R107K) alteration is located in exon 4 (coding exon 3) of the ARMC2 gene. This alteration results from a G to A substitution at nucleotide position 320, causing the arginine (R) at amino acid position 107 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.29
Dann	Benign	0.47
DEOGEN2	Benign	0.0084	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.91	N;N
REVEL	Benign	0.070
Sift	Benign	0.95	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.12
MutPred		0.17		Gain of ubiquitination at R107 (P = 7e-04);Gain of ubiquitination at R107 (P = 7e-04);
MVP		0.24
MPC		0.13
ClinPred		0.076	T
GERP RS		-0.40
Varity_R		0.035
gMVP		0.10

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: rs1776097078; hg19: chr6-109190055;