rs138132875

Variant names:

• chr1-108929693-A-G
• rs138132875
• NM_001377458.1:c.*2854T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PP3_Moderate BP6_Very_Strong BS1

The NM_013296.5(GPSM2):​c.1816-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,612,714 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: GPSM2 NM_013296.5 splice_region, intron
• Scores: Splicing: ADA: 0.7503
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.120
• Publications: 0 publications found

Genes affected

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]

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]

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 -10 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• BP6: Variant 1-108929693-A-G is Benign according to our data. Variant chr1-108929693-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00222 (338/152320) while in subpopulation AFR AF = 0.00791 (329/41568). AF 95% confidence interval is 0.00721. There are 1 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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
	CLCC1	NM_001377458.1	MANE Select	c.*2854T>C		3_prime_UTR	Exon 13 of 13	NP_001364387.1	Q96S66-1
	GPSM2	NM_013296.5	MANE Select	c.1816-8A>G		splice_region intron	N/A	NP_037428.3
	CLCC1	NM_001048210.3		c.*2854T>C		3_prime_UTR	Exon 12 of 12	NP_001041675.1	Q96S66-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCC1	ENST00000369969.7	TSL:5 MANE Select	c.*2854T>C		3_prime_UTR	Exon 13 of 13	ENSP00000358986.3	Q96S66-1
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.1816-8A>G		splice_region intron	N/A	ENSP00000264126.3	P81274
	CLCC1	ENST00000356970.6	TSL:5	c.*2854T>C		3_prime_UTR	Exon 12 of 12	ENSP00000349456.2	Q96S66-1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000558 AC: 139 AN: 249246 AF XY: 0.000459

Gnomad AFR exome AF: 0.00791

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000213 AC: 311 AN: 1460394 Hom.: 0 Cov.: 29 AF XY: 0.000180 AC XY: 131 AN XY: 726568

African (AFR) AF: 0.00813 AC: 272 AN: 33452

American (AMR) AF: 0.000291 AC: 13 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110846

Other (OTH) AF: 0.000331 AC: 20 AN: 60344

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00219 AC XY: 163 AN XY: 74482

African (AFR) AF: 0.00791 AC: 329 AN: 41568

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.00272

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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)
-	-	1	GPSM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.75
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.54		Position offset: 8

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

Other links and lift over

dbSNP: rs138132875; hg19: chr1-109472315;