chr4-5562881-G-GGCATTCAAAAAGTTCTTCTTTTTC

Variant names:

• chr4-5562881-G-GGCATTCAAAAAGTTCTTCTTTTTC
• rs730882232
• NM_147127.5:c.3870_3893dupGAAAAAGAAGAACTTTTTGAATGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_147127.5(EVC2):​c.3870_3893dupGAAAAAGAAGAACTTTTTGAATGC​(p.Ala1298_Lys1299insLysLysLysAsnPheLeuAsnAla) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EVC2 NM_147127.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.03
• Publications: 1 publications found

Genes affected

EVC2 (HGNC:19747): (EvC ciliary complex subunit 2) This gene encodes a protein that functions in bone formation and skeletal development. Mutations in this gene, as well as in a neighboring gene that lies in a head-to-head configuration, cause Ellis-van Creveld syndrome, an autosomal recessive skeletal dysplasia that is also known as chondroectodermal dysplasia. Mutations in this gene also cause acrofacial dysostosis Weyers type, also referred to as Curry-Hall syndrome, a disease that combines limb and facial abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

EVC2 Gene-Disease associations (from GenCC):

• acrofacial dysostosis, Weyers type

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_147127.5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147127.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.3870_3893dupGAAAAAGAAGAACTTTTTGAATGC	p.Ala1298_Lys1299insLysLysLysAsnPheLeuAsnAla	disruptive_inframe_insertion	Exon 22 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.3630_3653dupGAAAAAGAAGAACTTTTTGAATGC	p.Ala1218_Lys1219insLysLysLysAsnPheLeuAsnAla	disruptive_inframe_insertion	Exon 22 of 22	NP_001159608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.3870_3893dupGAAAAAGAAGAACTTTTTGAATGC	p.Ala1298_Lys1299insLysLysLysAsnPheLeuAsnAla	disruptive_inframe_insertion	Exon 22 of 22	ENSP00000342144.5
	EVC2	ENST00000310917.6	TSL:1	c.3630_3653dupGAAAAAGAAGAACTTTTTGAATGC	p.Ala1218_Lys1219insLysLysLysAsnPheLeuAsnAla	disruptive_inframe_insertion	Exon 22 of 22	ENSP00000311683.2
	EVC2	ENST00000509670.1	TSL:1	n.*2263_*2286dupGAAAAAGAAGAACTTTTTGAATGC		non_coding_transcript_exon	Exon 23 of 23	ENSP00000423876.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Meckel-Gruber syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=65/35	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs730882232; hg19: chr4-5564608;