chr4-5562758-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_147127.5(EVC2):​c.*90C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,600,806 control chromosomes in the GnomAD database, including 19 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 0.0028 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 16 hom. )

Consequence

EVC2
NM_147127.5 3_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.822
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-1.0).
BP6
Variant 4-5562758-G-A is Benign according to our data. Variant chr4-5562758-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 348978.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00318 (4600/1448470) while in subpopulation NFE AF= 0.00353 (3924/1111304). AF 95% confidence interval is 0.00344. There are 16 homozygotes in gnomad4_exome. There are 2192 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EVC2NM_147127.5 linkc.*90C>T 3_prime_UTR_variant Exon 22 of 22 ENST00000344408.10 NP_667338.3 Q86UK5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EVC2ENST00000344408 linkc.*90C>T 3_prime_UTR_variant Exon 22 of 22 1 NM_147127.5 ENSP00000342144.5 Q86UK5-1
EVC2ENST00000310917 linkc.*90C>T 3_prime_UTR_variant Exon 22 of 22 1 ENSP00000311683.2 Q86UK5-2
EVC2ENST00000475313.5 linkn.3419+2500C>T intron_variant Intron 21 of 22 1 ENSP00000431981.1 A0A0C4DGE7
EVC2ENST00000509670.1 linkn.*2410C>T downstream_gene_variant 1 ENSP00000423876.1 E9PFT2

Frequencies

GnomAD3 genomes
AF:
0.00275
AC:
419
AN:
152218
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000627
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000850
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0164
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.00291
Gnomad OTH
AF:
0.00191
GnomAD4 exome
AF:
0.00318
AC:
4600
AN:
1448470
Hom.:
16
Cov.:
32
AF XY:
0.00304
AC XY:
2192
AN XY:
720868
show subpopulations
Gnomad4 AFR exome
AF:
0.000691
Gnomad4 AMR exome
AF:
0.000428
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000353
Gnomad4 FIN exome
AF:
0.0110
Gnomad4 NFE exome
AF:
0.00353
Gnomad4 OTH exome
AF:
0.00236
GnomAD4 genome
AF:
0.00275
AC:
419
AN:
152336
Hom.:
3
Cov.:
32
AF XY:
0.00321
AC XY:
239
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000625
Gnomad4 AMR
AF:
0.000849
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0164
Gnomad4 NFE
AF:
0.00291
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00228
Hom.:
0
Bravo
AF:
0.00159
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1
Jun 10, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-1.0
CADD
Benign
0.15
DANN
Benign
0.68

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs115810595; hg19: chr4-5564485; API