NM_013296.5:c.1062+1G>A

Variant names:

• chr1-108903235-G-A
• rs777695770
• NM_013296.5:c.1062+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_013296.5(GPSM2):​c.1062+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,365,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: GPSM2 NM_013296.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.56
• Publications: 0 publications found

Genes affected

GPSM2 (HGNC:29501): (G protein signaling modulator 2) The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

CLCC1 (HGNC:29675): (chloride channel CLIC like 1) Predicted to enable chloride channel activity. Predicted to be involved in chloride transport. Located in endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane. Implicated in retinitis pigmentosa 32. [provided by Alliance of Genome Resources, Apr 2022]

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013296.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	NM_013296.5	MANE Select	c.1062+1G>A		splice_donor intron	N/A	NP_037428.3
	GPSM2	NM_001321038.2		c.1062+1G>A		splice_donor intron	N/A	NP_001307967.1
	GPSM2	NM_001321039.3		c.1062+1G>A		splice_donor intron	N/A	NP_001307968.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.1062+1G>A		splice_donor intron	N/A	ENSP00000264126.3
	GPSM2	ENST00000675776.1		n.1558G>A		non_coding_transcript_exon	Exon 9 of 9
	GPSM2	ENST00000675829.1		n.2760G>A		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1365542 Hom.: 0 Cov.: 22 AF XY: 0.00000146 AC XY: 1 AN XY: 684472

African (AFR) AF: 0.00 AC: 0 AN: 31632

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 39226

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1024512

Other (OTH) AF: 0.00 AC: 0 AN: 57130

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.6
GERP RS		5.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777695770; hg19: chr1-109445857;