rs79730689
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_013296.5(GPSM2):c.1739C>T(p.Ser580Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000273 in 1,613,632 control chromosomes in the GnomAD database, including 2 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 0.0014 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 1 hom. )
Consequence
GPSM2
NM_013296.5 missense
NM_013296.5 missense
Scores
1
4
13
Clinical Significance
Conservation
PhyloP100: 5.62
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.006495118).
BP6
?
Variant 1-108924138-C-T is Benign according to our data. Variant chr1-108924138-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178376.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=2}.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00139 (212/152166) while in subpopulation AFR AF= 0.00484 (201/41502). AF 95% confidence interval is 0.00429. There are 1 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPSM2 | NM_013296.5 | c.1739C>T | p.Ser580Leu | missense_variant | 14/15 | ENST00000264126.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPSM2 | ENST00000264126.9 | c.1739C>T | p.Ser580Leu | missense_variant | 14/15 | 1 | NM_013296.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00137 AC: 208AN: 152048Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000422 AC: 106AN: 251288Hom.: 0 AF XY: 0.000353 AC XY: 48AN XY: 135798
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GnomAD4 exome AF: 0.000156 AC: 228AN: 1461466Hom.: 1 Cov.: 31 AF XY: 0.000146 AC XY: 106AN XY: 727084
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GnomAD4 genome ? AF: 0.00139 AC: 212AN: 152166Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99AN XY: 74374
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 05, 2017 | The p.Ser580Leu variant (rs79730689) has not been reported in the medical literature. This variant is found in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.47% in the African population (identified in 112 out of 24,016 chromosomes), and is listed in ClinVar with conflicting interpretations of pathogenicity (likely benign/uncertain significance; Variant ID: 178376). The serine at codon 580 is moderately conserved considering 12 species (Alamut software v2.9.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). While this variant appears to be a benign polymorphism common in the African population, the available evidence is insufficient to classify the clinical significance of this variant with certainty. - |
Chudley-McCullough syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | Ser580Leu in exon 14 of GPSM2: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (19/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs79730689). - |
GPSM2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 23, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N
REVEL
Uncertain
Sift
Benign
T;.;T
Sift4G
Benign
T;.;T
Polyphen
B;B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at