1-108901820-A-G

Variant names:

• chr1-108901820-A-G
• rs338489
• NM_013296.5:c.828A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013296.5(GPSM2):​c.828A>G​(p.Lys276Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.00515 in 1,612,284 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (166 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (150 hom.)
• Consequence: GPSM2 NM_013296.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.38
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-108901820-A-G is Benign according to our data. Variant chr1-108901820-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0838 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	NM_013296.5	MANE Select	c.828A>G	p.Lys276Lys	synonymous	Exon 8 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.828A>G	p.Lys276Lys	synonymous	Exon 8 of 15	NP_001307967.1
	GPSM2	NM_001321039.3		c.828A>G	p.Lys276Lys	synonymous	Exon 8 of 16	NP_001307968.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.828A>G	p.Lys276Lys	synonymous	Exon 8 of 15	ENSP00000264126.3
	GPSM2	ENST00000674914.1		c.879A>G	p.Lys293Lys	synonymous	Exon 9 of 16	ENSP00000501579.1
	GPSM2	ENST00000675087.1		c.879A>G	p.Lys293Lys	synonymous	Exon 10 of 17	ENSP00000502020.1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3846 AN: 152156 Hom.: 165 Cov.: 31

Gnomad AFR AF: 0.0862

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00744 AC: 1870 AN: 251386 AF XY: 0.00536

Gnomad AFR exome AF: 0.0921

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00724

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00304 AC: 4444 AN: 1460010 Hom.: 150 Cov.: 29 AF XY: 0.00271 AC XY: 1968 AN XY: 726520

African (AFR) AF: 0.0900 AC: 3006 AN: 33394

American (AMR) AF: 0.00590 AC: 264 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00586 AC: 153 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5766

European-Non Finnish (NFE) AF: 0.000440 AC: 489 AN: 1110370

Other (OTH) AF: 0.00767 AC: 463 AN: 60340

GnomAD4 genome AF: 0.0253 AC: 3854 AN: 152274 Hom.: 166 Cov.: 31 AF XY: 0.0249 AC XY: 1854 AN XY: 74460

African (AFR) AF: 0.0862 AC: 3581 AN: 41544

American (AMR) AF: 0.0105 AC: 160 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68016

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0111 Hom.: 97

Bravo AF: 0.0284

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.7
DANN	Benign	0.72
PhyloP100		4.4
PromoterAI		0.0091	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs338489; hg19: chr1-109444442;