rs2234473

Variant names:

• chr11-65867062-G-A
• rs2234473
• NM_016938.5:c.1188C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_016938.5(EFEMP2):​c.1188C>T​(p.Ser396Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,614,094 control chromosomes in the GnomAD database, including 8 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 0.0017 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: EFEMP2 NM_016938.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.00400
• Publications: 4 publications found

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]

MUS81 (HGNC:29814): (MUS81 structure-specific endonuclease subunit) This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-65867062-G-A is Benign according to our data. Variant chr11-65867062-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305377.
• BP7: Synonymous conserved (PhyloP=0.004 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00167 (255/152274) while in subpopulation NFE AF = 0.00175 (119/68010). AF 95% confidence interval is 0.00149. There are 2 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016938.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	NM_016938.5	MANE Select	c.1188C>T	p.Ser396Ser	synonymous	Exon 11 of 11	NP_058634.4	O95967
	EFEMP2	NR_037718.2		n.1313C>T		non_coding_transcript_exon	Exon 11 of 12
	MUS81	NR_146598.2		n.1813-195G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.1188C>T	p.Ser396Ser	synonymous	Exon 11 of 11	ENSP00000309953.6	O95967
	EFEMP2	ENST00000531972.5	TSL:1	n.1188C>T		non_coding_transcript_exon	Exon 11 of 12	ENSP00000435295.1	O95967
	EFEMP2	ENST00000907927.1		c.1407C>T	p.Ser469Ser	synonymous	Exon 12 of 12	ENSP00000577986.1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152156 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00215 AC: 539 AN: 251228 AF XY: 0.00206

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00246 AC: 3593 AN: 1461820 Hom.: 6 Cov.: 31 AF XY: 0.00240 AC XY: 1746 AN XY: 727208

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00974 AC: 520 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00266 AC: 2959 AN: 1111998

Other (OTH) AF: 0.00142 AC: 86 AN: 60394

GnomAD4 genome AF: 0.00167 AC: 255 AN: 152274 Hom.: 2 Cov.: 33 AF XY: 0.00205 AC XY: 153 AN XY: 74454

African (AFR) AF: 0.000505 AC: 21 AN: 41554

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00175 AC: 119 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00109

EpiCase AF: 0.00196

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Cutis laxa, autosomal recessive, type 1B (5)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	EFEMP2-related disorder (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		0.0040
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2234473; hg19: chr11-65634533; COSMIC: COSV57261728; COSMIC: COSV57261728;