Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBS1BS2

The NM_013296.5(GPSM2):c.1566_1568delAAC(p.Thr523del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.49

Publications

1 publications found

Variant links:

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]

GPSM2 links:

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]

CLCC1 links:

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]

AKNAD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPSM2	NM_013296.5	MANE Select	c.1566_1568delAAC	p.Thr523del	disruptive_inframe_deletion	Exon 13 of 15	NP_037428.3
GPSM2	NM_001321038.2		c.1566_1568delAAC	p.Thr523del	disruptive_inframe_deletion	Exon 13 of 15	NP_001307967.1
GPSM2	NM_001321039.3		c.1566_1568delAAC	p.Thr523del	disruptive_inframe_deletion	Exon 13 of 16	NP_001307968.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.1566_1568delAAC	p.Thr523del	disruptive_inframe_deletion	Exon 13 of 15	ENSP00000264126.3
GPSM2	ENST00000674914.1		c.1617_1619delAAC	p.Thr540del	disruptive_inframe_deletion	Exon 14 of 16	ENSP00000501579.1
GPSM2	ENST00000675087.1		c.1617_1619delAAC	p.Thr540del	disruptive_inframe_deletion	Exon 15 of 17	ENSP00000502020.1

Frequencies

GnomAD3 genomes

AF:

0.000794

AC:

102

AN:

128476

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00146

AC:

356

AN:

243040

AF XY:

0.00148

show subpopulations

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 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.:

AF XY:

0.000707

AC XY:

514

AN XY:

726858

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33446

American (AMR)

AF:

0.000380

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0221

AC:

874

AN:

39632

South Asian (SAS)

AF:

0.000893

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111322

Other (OTH)

AF:

0.000977

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000786

AC:

101

AN:

128530

Hom.:

Cov.:

AF XY:

0.000920

AC XY:

AN XY:

63030

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

27308

American (AMR)

AF:

0.000212

AC:

AN:

14144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3024

East Asian (EAS)

AF:

0.0161

AC:

AN:

5162

South Asian (SAS)

AF:

0.000226

AC:

AN:

4430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.0000322

AC:

AN:

62136

Other (OTH)

AF:

0.00160

AC:

AN:

1872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.000654

Asia WGS

AF:

0.00465

AC:

AN:

3452

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Chudley-McCullough syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs199964596

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over