2-27080817-G-C

Variant names:

• chr2-27080817-G-C
• rs770482130
• NM_007046.4:c.376G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007046.4(EMILIN1):​c.376G>C​(p.Gly126Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G126S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EMILIN1 NM_007046.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.80
• Publications: 0 publications found

Genes affected

EMILIN1 (HGNC:19880): (elastin microfibril interfacer 1) This gene encodes an extracellular matrix glycoprotein that is characterized by an N-terminal microfibril interface domain, a coiled-coiled alpha-helical domain, a collagenous domain and a C-terminal globular C1q domain. The encoded protein associates with elastic fibers at the interface between elastin and microfibrils and may play a role in the development of elastic tissues including large blood vessels, dermis, heart and lung. [provided by RefSeq, Sep 2009]

EMILIN1 Gene-Disease associations (from GenCC):

• arterial tortuosity-bone fragility syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronopathy, distal hereditary motor, autosomal dominant 10

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007046.4. 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
	EMILIN1	NM_007046.4	MANE Select	c.376G>C	p.Gly126Arg	missense	Exon 3 of 8	NP_008977.1	Q9Y6C2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMILIN1	ENST00000380320.9	TSL:1 MANE Select	c.376G>C	p.Gly126Arg	missense	Exon 3 of 8	ENSP00000369677.4	Q9Y6C2-1
	EMILIN1	ENST00000957377.1		c.376G>C	p.Gly126Arg	missense	Exon 3 of 8	ENSP00000627436.1
	EMILIN1	ENST00000957375.1		c.376G>C	p.Gly126Arg	missense	Exon 3 of 7	ENSP00000627434.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.84		Gain of solvent accessibility (P = 0.0789)
MVP		0.84
MPC		0.81
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.31
gMVP		0.77
Mutation Taster		=32/68	disease causing

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: rs770482130; hg19: chr2-27303685;