rs201866563

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_001077415.3(CRELD1):c.575G>A(p.Cys192Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

CRELD1
NM_001077415.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 9.53

Variant links:

Genes affected

CRELD1 (HGNC:14630): (cysteine rich with EGF like domains 1) This gene encodes a member of a subfamily of epidermal growth factor-related proteins. The encoded protein is characterized by a cysteine-rich with epidermal growth factor-like domain. This protein may function as a cell adhesion molecule. Mutations in this gene are the cause of atrioventricular septal defect. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

CRELD1 links:

ENSG00000288550 (HGNC:):

ENSG00000288550 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRELD1	NM_001077415.3 linkuse as main transcript	c.575G>A	p.Cys192Tyr	missense_variant	6/11	ENST00000452070.6	NP_001070883.2	Q96HD1-1A0A024R2G1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CRELD1	ENST00000452070.6 linkuse as main transcript	c.575G>A	p.Cys192Tyr	missense_variant	6/11	2	NM_001077415.3	ENSP00000393643.2	Q96HD1-1
ENSG00000288550	ENST00000683484.1 linkuse as main transcript	n.*223G>A		non_coding_transcript_exon_variant	19/24			ENSP00000507040.1	A0A804HIF2
ENSG00000288550	ENST00000683484.1 linkuse as main transcript	n.*223G>A		3_prime_UTR_variant	19/24			ENSP00000507040.1	A0A804HIF2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251352

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000344

AC:

503

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000341

AC XY:

248

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000434

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000125

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000355

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Jeffries-Lakhani neurodevelopmental syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	May 24, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 29, 2024	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CRELD1: PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32437232, 37947183) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2024

The c.575G>A (p.C192Y) alteration is located in coding exon 5 of the CRELD1 gene. This alteration results from a G to A substitution at nucleotide position 575, causing the cysteine (C) at amino acid position 192 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of 0.018% (52/282700) total alleles studied. The highest observed frequency was 0.037% (48/129056) of European (non-Finnish) alleles. This variant has been reported as a homozygous finding in a female with epileptic encephalopathy (de Kovel, 2016). In a cohort of individuals with biallelic variants in CRELD1 presenting with early-onset neurodevelopmental disorder features and slowly progressive non-neurologic features, this was detected in compound heterozygous form in nine probands and as a homozygous finding in one other proband (Jeffries, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Atrioventricular septal defect, susceptibility to, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 238218). This variant has not been reported in the literature in individuals affected with CRELD1-related conditions. This variant is present in population databases (rs201866563, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 192 of the CRELD1 protein (p.Cys192Tyr). -

CRELD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Feb 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T;T;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

.;.;T;T

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.061

MutationAssessor

Pathogenic

3.4

M;M;M;M

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-11

D;D;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.96

MVP

0.95

MPC

0.89

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.98

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over