chrX-101656961-C-G

Variant names:

• chrX-101656961-C-G
• rs137976844
• NM_177949.4:c.628G>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_177949.4(ARMCX2):​c.628G>C​(p.Gly210Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,209,567 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 273 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., 14 hem., cov: 24)
  • Exomes 𝑓: 0.00076 (0 hom. 259 hem.)
• Consequence: ARMCX2 NM_177949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:2
• Conservation: PhyloP100: -2.27

Genes affected

ARMCX2 (HGNC:16869): (armadillo repeat containing X-linked 2) This gene encodes a protein containing a potential N-terminal transmembrane domain and multiple armadillo (arm) repeats. Proteins containing arm repeats are involved in development, maintenance of tissue integrity, and tumorigenesis. This gene is located in a cluster of related genes on chromosome X. There is a pseudogene for this gene on chromosome 7. Alternative splicing in the 5' UTR results in multiple transcript variants encoding the same protein. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040902793).
• BS2: High Hemizygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMCX2	NM_177949.4	c.628G>C	p.Gly210Arg	missense_variant	Exon 6 of 6	ENST00000356824.9	NP_808818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMCX2	ENST00000356824.9	c.628G>C	p.Gly210Arg	missense_variant	Exon 6 of 6	1	NM_177949.4	ENSP00000349281.4

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 66 AN: 111627 Hom.: 0 Cov.: 24 AF XY: 0.000414 AC XY: 14 AN XY: 33805

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.0234

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000888

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000439 AC: 79 AN: 179970 Hom.: 0 AF XY: 0.000394 AC XY: 26 AN XY: 65942

Gnomad AFR exome AF: 0.0000790

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000757 AC: 831 AN: 1097940 Hom.: 0 Cov.: 34 AF XY: 0.000713 AC XY: 259 AN XY: 363346

Gnomad4 AFR exome AF: 0.0000757

Gnomad4 AMR exome AF: 0.000256

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: 0.000944

Gnomad4 OTH exome AF: 0.000542

GnomAD4 genome AF: 0.000591 AC: 66 AN: 111627 Hom.: 0 Cov.: 24 AF XY: 0.000414 AC XY: 14 AN XY: 33805

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000888

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000574

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00138 AC: 4

ExAC AF: 0.000495 AC: 60

EpiCase AF: 0.000872

EpiControl AF: 0.000712

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.628G>C (p.G210R) alteration is located in exon 6 (coding exon 1) of the ARMCX2 gene. This alteration results from a G to C substitution at nucleotide position 628, causing the glycine (G) at amino acid position 210 to be replaced by an arginine (R). 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	0.075
BayesDel_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.027
DANN	Benign	0.23
DEOGEN2	Benign	0.013	T;T;T
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.37	.;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.0070
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.049
MutPred		0.27		Loss of catalytic residue at V211 (P = 0.0398);Loss of catalytic residue at V211 (P = 0.0398);Loss of catalytic residue at V211 (P = 0.0398);
MVP		0.068
MPC		0.45
ClinPred		0.0043	T
GERP RS		-6.3
Varity_R		0.052
gMVP		0.072

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: rs137976844; hg19: chrX-100911947;