rs2234457

chr11-65871992-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd 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: 529 AN: 152110 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000914 AC: 143 AN: 156526 Hom.: 0 AF XY: 0.000753 AC XY: 62 AN XY: 82348

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000329 AC: 460 AN: 1399402 Hom.: 1 Cov.: 31 AF XY: 0.000288 AC XY: 199 AN XY: 690224

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.00118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.000776

GnomAD4 genome AF: 0.00347 AC: 528 AN: 152228 Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74430

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000874 Hom.: 3

Bravo AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	11
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2234457; hg19: chr11-65639463;