1-108929928-G-A

Variant names:

• chr1-108929928-G-A
• rs140949805
• NM_013296.5:c.2043G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_013296.5(GPSM2):​c.2043G>A​(p.Ser681Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,254 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: GPSM2 NM_013296.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.637
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-108929928-G-A is Benign according to our data. Variant chr1-108929928-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45566.
• BP7: Synonymous conserved (PhyloP=0.637 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0017 (259/152202) while in subpopulation AFR AF = 0.00238 (99/41514). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.2043G>A	p.Ser681Ser	synonymous	Exon 15 of 15	NP_037428.3
	CLCC1	NM_001377458.1	MANE Select	c.*2619C>T		3_prime_UTR	Exon 13 of 13	NP_001364387.1
	GPSM2	NM_001321038.2		c.2043G>A	p.Ser681Ser	synonymous	Exon 15 of 15	NP_001307967.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.2043G>A	p.Ser681Ser	synonymous	Exon 15 of 15	ENSP00000264126.3
	CLCC1	ENST00000369969.7	TSL:5 MANE Select	c.*2619C>T		3_prime_UTR	Exon 13 of 13	ENSP00000358986.3
	GPSM2	ENST00000674914.1		c.2094G>A	p.Ser698Ser	synonymous	Exon 16 of 16	ENSP00000501579.1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00154 AC: 384 AN: 248730 AF XY: 0.00148

Gnomad AFR exome AF: 0.00242

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00125 AC: 1824 AN: 1461052 Hom.: 4 Cov.: 30 AF XY: 0.00129 AC XY: 939 AN XY: 726850

African (AFR) AF: 0.00245 AC: 82 AN: 33456

American (AMR) AF: 0.000716 AC: 32 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26118

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39678

South Asian (SAS) AF: 0.00117 AC: 101 AN: 86224

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53408

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5766

European-Non Finnish (NFE) AF: 0.00129 AC: 1435 AN: 1111334

Other (OTH) AF: 0.00159 AC: 96 AN: 60364

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74428

African (AFR) AF: 0.00238 AC: 99 AN: 41514

American (AMR) AF: 0.00144 AC: 22 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10574

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00176 AC: 120 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00185

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00225

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	1	-	Chudley-McCullough syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
DANN	Benign	0.58
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs140949805; hg19: chr1-109472550;