rs2234457
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_016938.5(EFEMP2):c.138C>T(p.Asp46=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,551,630 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0035 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 1 hom. )
Consequence
EFEMP2
NM_016938.5 synonymous
NM_016938.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.685
Genes affected
EFEMP2 (HGNC:3219): (EGF containing fibulin extracellular matrix protein 2) A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement and determination of cell fate during development. The protein encoded by this gene contains four EGF2 domains and six calcium-binding EGF2 domains. This gene is necessary for elastic fiber formation and connective tissue development. Defects in this gene are cause of an autosomal recessive cutis laxa syndrome. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 11-65871992-G-A is Benign according to our data. Variant chr11-65871992-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-65871992-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.685 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00347 (528/152228) while in subpopulation AFR AF= 0.012 (498/41518). AF 95% confidence interval is 0.0111. There are 2 homozygotes in gnomad4. There are 263 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EFEMP2 | NM_016938.5 | c.138C>T | p.Asp46= | synonymous_variant | 3/11 | ENST00000307998.11 | |
EFEMP2 | NR_037718.2 | n.263C>T | non_coding_transcript_exon_variant | 3/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EFEMP2 | ENST00000307998.11 | c.138C>T | p.Asp46= | synonymous_variant | 3/11 | 1 | NM_016938.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00348 AC: 529AN: 152110Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000914 AC: 143AN: 156526Hom.: 0 AF XY: 0.000753 AC XY: 62AN XY: 82348
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GnomAD4 exome AF: 0.000329 AC: 460AN: 1399402Hom.: 1 Cov.: 31 AF XY: 0.000288 AC XY: 199AN XY: 690224
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GnomAD4 genome AF: 0.00347 AC: 528AN: 152228Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 263AN XY: 74430
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cutis laxa, autosomal recessive, type 1B Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 24, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2021 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 24, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at