rs199964596

chr1-108922534-TCAA-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_013296.5(GPSM2):c.1566_1568del(p.Thr523del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,589,560 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (9 hom.)
• Consequence: GPSM2 NM_013296.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.49

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]

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]

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_013296.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 1-108922534-TCAA-T is Benign according to our data. Variant chr1-108922534-TCAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 517193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000786 (101/128530) while in subpopulation EAS AF= 0.0161 (83/5162). AF 95% confidence interval is 0.0133. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPSM2	NM_013296.5	c.1566_1568del	p.Thr523del	inframe_deletion	13/15	ENST00000264126.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPSM2	ENST00000264126.9	c.1566_1568del	p.Thr523del	inframe_deletion	13/15	1	NM_013296.5	P1

Frequencies

GnomAD3 genomes AF: 0.000794 AC: 102 AN: 128476 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000212

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.000226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000322

Gnomad OTH AF: 0.00162

GnomAD3 exomes AF: 0.00146 AC: 356 AN: 243040 Hom.: 4 AF XY: 0.00148 AC XY: 195 AN XY: 131718

Gnomad AFR exome AF: 0.000212

Gnomad AMR exome AF: 0.000417

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0165

Gnomad SAS exome AF: 0.00104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.000677

GnomAD4 exome AF: 0.000716 AC: 1046 AN: 1461030 Hom.: 9 AF XY: 0.000707 AC XY: 514 AN XY: 726858

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0221

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000786 AC: 101 AN: 128530 Hom.: 0 Cov.: 32 AF XY: 0.000920 AC XY: 58 AN XY: 63030

Gnomad4 AFR AF: 0.000330

Gnomad4 AMR AF: 0.000212

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0161

Gnomad4 SAS AF: 0.000226

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000322

Gnomad4 OTH AF: 0.00160

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000654

Asia WGS AF: 0.00465 AC: 16 AN: 3452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 12, 2017

p.Thr523del in exon 13 of GPSM2: This variant is not expected to have clinical s ignificance because it has been identified in 1.8% (158/8654) of East Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs199964596). -

Chudley-McCullough syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs199964596; hg19: chr1-109465156;