chr4-5708392-G-T

Variant names:

• chr4-5708392-G-T
• rs544397395
• NM_147127.5:c.122C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_147127.5(EVC2):​c.122C>A​(p.Pro41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,496,282 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P41T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (22 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.448
• Publications: 2 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061277747).
• BP6: Variant 4-5708392-G-T is Benign according to our data. Variant chr4-5708392-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193503.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00281 (428/152100) while in subpopulation NFE AF = 0.00453 (308/67948). AF 95% confidence interval is 0.00412. There are 2 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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_147127.5. 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
	EVC2	NM_147127.5	MANE Select	c.122C>A	p.Pro41His	missense	Exon 1 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.-13+437C>A		intron	N/A	NP_001159608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.122C>A	p.Pro41His	missense	Exon 1 of 22	ENSP00000342144.5
	EVC2	ENST00000310917.6	TSL:1	c.-13+437C>A		intron	N/A	ENSP00000311683.2
	EVC2	ENST00000475313.5	TSL:1	n.-13+437C>A		intron	N/A	ENSP00000431981.1

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 428 AN: 151984 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00361 AC: 331 AN: 91778 AF XY: 0.00352

Gnomad AFR exome AF: 0.000659

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000588

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00484 AC: 6506 AN: 1344182 Hom.: 22 Cov.: 30 AF XY: 0.00470 AC XY: 3115 AN XY: 662254

African (AFR) AF: 0.000698 AC: 19 AN: 27240

American (AMR) AF: 0.00135 AC: 42 AN: 31036

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 441 AN: 23408

East Asian (EAS) AF: 0.00 AC: 0 AN: 31538

South Asian (SAS) AF: 0.00 AC: 0 AN: 74740

European-Finnish (FIN) AF: 0.000660 AC: 22 AN: 33314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4482

European-Non Finnish (NFE) AF: 0.00540 AC: 5733 AN: 1062352

Other (OTH) AF: 0.00444 AC: 249 AN: 56072

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152100 Hom.: 2 Cov.: 32 AF XY: 0.00248 AC XY: 184 AN XY: 74342

African (AFR) AF: 0.000819 AC: 34 AN: 41532

American (AMR) AF: 0.00131 AC: 20 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 67948

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00459 Hom.: 0

Bravo AF: 0.00280

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00441 AC: 17

ExAC AF: 0.00155 AC: 57

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	1	Ellis-van Creveld syndrome (2)
-	-	2	not specified (2)
-	-	1	Curry-Hall syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.45
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.14
MVP		0.77
MPC		0.11
ClinPred		0.033	T
GERP RS		1.9
PromoterAI		0.013	Neutral
Varity_R		0.065
gMVP		0.15
Mutation Taster		=100/0	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: rs544397395; hg19: chr4-5710119; COSMIC: COSV53832620; COSMIC: COSV53832620;