X-13777355-G-C

Variant names:

• chrX-13777355-G-C
• NM_001001995.3:c.768C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001995.3(GPM6B):​c.768C>G​(p.Asn256Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GPM6B NM_001001995.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0470

Genes affected

GPM6B (HGNC:4461): (glycoprotein M6B) This gene encodes a membrane glycoprotein that belongs to the proteolipid protein family. Proteolipid protein family members are expressed in most brain regions and are thought to be involved in cellular housekeeping functions such as membrane trafficking and cell-to-cell communication. This protein may also be involved in osteoblast differentiation. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are located on chromosomes Y and 22. [provided by RefSeq, Jan 2016]

OFD1 (HGNC:2567): (OFD1 centriole and centriolar satellite protein) This gene is located on the X chromosome and encodes a centrosomal protein. A knockout mouse model has been used to study the effect of mutations in this gene. The mouse gene is also located on the X chromosome, however, unlike the human gene it is not subject to X inactivation. Mutations in this gene are associated with oral-facial-digital syndrome type I and Simpson-Golabi-Behmel syndrome type 2. Many pseudogenes have been identified; a single pseudogene is found on chromosome 5 while as many as fifteen have been found on the Y chromosome. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21857217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPM6B	NM_001001995.3	c.768C>G	p.Asn256Lys	missense_variant	Exon 6 of 8	ENST00000316715.9	NP_001001995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPM6B	ENST00000316715.9	c.768C>G	p.Asn256Lys	missense_variant	Exon 6 of 8	2	NM_001001995.3	ENSP00000316861.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.768C>G (p.N256K) alteration is located in exon 6 (coding exon 6) of the GPM6B gene. This alteration results from a C to G substitution at nucleotide position 768, causing the asparagine (N) at amino acid position 256 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	0.21
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	5.5
DANN	Benign	0.97
DEOGEN2	Benign	0.39	.;.;.;.;T;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;D;T;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.77	N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.33	T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T
Polyphen		0.12, 0.31, 0.16, 0.15	.;B;B;B;B;.
Vest4		0.49
MutPred		0.45		.;.;Gain of solvent accessibility (P = 0.0086);.;.;.;
MVP		0.73
MPC		1.1
ClinPred		0.42	T
GERP RS		-0.025
Varity_R		0.23
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-13795474;