rs9727773

Variant names:

• chr1-108897090-T-C
• rs9727773
• NM_013296.5:c.278+5T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_013296.5(GPSM2):​c.278+5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,562,598 control chromosomes in the GnomAD database, including 383 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (215 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (168 hom.)
• Consequence: GPSM2 NM_013296.5 splice_region, intron
• Scores: Splicing: ADA: 0.004009
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.160
• Publications: 1 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-108897090-T-C is Benign according to our data. Variant chr1-108897090-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0951 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	NM_013296.5	MANE Select	c.278+5T>C		splice_region intron	N/A	NP_037428.3
	GPSM2	NM_001321038.2		c.278+5T>C		splice_region intron	N/A	NP_001307967.1	P81274
	GPSM2	NM_001321039.3		c.278+5T>C		splice_region intron	N/A	NP_001307968.1	P81274

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.278+5T>C		splice_region intron	N/A	ENSP00000264126.3	P81274
	GPSM2	ENST00000674914.1		c.329+5T>C		splice_region intron	N/A	ENSP00000501579.1	A0A6Q8PF02
	GPSM2	ENST00000675087.1		c.329+5T>C		splice_region intron	N/A	ENSP00000502020.1	A0A6Q8PF02

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4306 AN: 152210 Hom.: 216 Cov.: 32

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00794 AC: 1982 AN: 249544 AF XY: 0.00589

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00640

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.000383

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00294 AC: 4140 AN: 1410270 Hom.: 168 Cov.: 24 AF XY: 0.00249 AC XY: 1758 AN XY: 704678

African (AFR) AF: 0.0975 AC: 3161 AN: 32430

American (AMR) AF: 0.00665 AC: 297 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85140

European-Finnish (FIN) AF: 0.000957 AC: 51 AN: 53298

Middle Eastern (MID) AF: 0.00444 AC: 20 AN: 4508

European-Non Finnish (NFE) AF: 0.000236 AC: 252 AN: 1066356

Other (OTH) AF: 0.00594 AC: 348 AN: 58582

GnomAD4 genome AF: 0.0283 AC: 4306 AN: 152328 Hom.: 215 Cov.: 32 AF XY: 0.0269 AC XY: 2002 AN XY: 74496

African (AFR) AF: 0.0976 AC: 4059 AN: 41572

American (AMR) AF: 0.0101 AC: 155 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68024

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0134 Hom.: 130

Bravo AF: 0.0322

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Chudley-McCullough syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		0.16
PromoterAI		0.041	Neutral
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0040
dbscSNV1_RF	Benign	0.062
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

Other links and lift over

dbSNP: rs9727773; hg19: chr1-109439712;