chr4-5562641-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_147127.5(EVC2):​c.*207A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000621 in 1,435,260 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 0.0025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00040 ( 3 hom. )

Consequence

EVC2
NM_147127.5 3_prime_UTR

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.596
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
Variant 4-5562641-T-C is Benign according to our data. Variant chr4-5562641-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 899532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0025 (381/152170) while in subpopulation AFR AF= 0.00761 (316/41532). AF 95% confidence interval is 0.00692. There are 0 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EVC2NM_147127.5 linkuse as main transcriptc.*207A>G 3_prime_UTR_variant 22/22 ENST00000344408.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EVC2ENST00000344408.10 linkuse as main transcriptc.*207A>G 3_prime_UTR_variant 22/221 NM_147127.5 P2Q86UK5-1
EVC2ENST00000310917.6 linkuse as main transcriptc.*207A>G 3_prime_UTR_variant 22/221 A2Q86UK5-2
EVC2ENST00000475313.5 linkuse as main transcriptc.3419+2617A>G intron_variant, NMD_transcript_variant 1

Frequencies

GnomAD3 genomes
AF:
0.00250
AC:
380
AN:
152052
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00761
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00308
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00239
GnomAD4 exome
AF:
0.000398
AC:
511
AN:
1283090
Hom.:
3
Cov.:
31
AF XY:
0.000357
AC XY:
223
AN XY:
624508
show subpopulations
Gnomad4 AFR exome
AF:
0.00979
Gnomad4 AMR exome
AF:
0.00183
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000473
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000124
Gnomad4 OTH exome
AF:
0.00106
GnomAD4 genome
AF:
0.00250
AC:
381
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.00251
AC XY:
187
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00761
Gnomad4 AMR
AF:
0.00307
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00236
Alfa
AF:
0.000861
Hom.:
0
Bravo
AF:
0.00287
Asia WGS
AF:
0.000289
AC:
2
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.92
CADD
Benign
6.6
DANN
Benign
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs73072282; hg19: chr4-5564368; API