22-41229711-C-T

Variant names:

• chr22-41229711-C-T
• rs769398487
• NM_138481.2:c.2282G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138481.2(CHADL):​c.2282G>A​(p.Arg761His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,612,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: CHADL NM_138481.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.727

Genes affected

CHADL (HGNC:25165): (chondroadherin like) Enables collagen binding activity and collagen fibril binding activity. Involved in negative regulation of collagen fibril organization. Located in collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

L3MBTL2 (HGNC:18594): (L3MBTL histone methyl-lysine binding protein 2) Enables methylated histone binding activity. Predicted to be involved in negative regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including ectoderm development; regulation of histone modification; and stem cell proliferation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04518169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHADL	NM_138481.2	c.2282G>A	p.Arg761His	missense_variant	Exon 6 of 6	ENST00000216241.14	NP_612490.1
L3MBTL2	NM_031488.5	c.2005+55C>T		intron_variant	Intron 16 of 16	ENST00000216237.10	NP_113676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHADL	ENST00000216241.14	c.2282G>A	p.Arg761His	missense_variant	Exon 6 of 6	1	NM_138481.2	ENSP00000216241.9
L3MBTL2	ENST00000216237.10	c.2005+55C>T		intron_variant	Intron 16 of 16	1	NM_031488.5	ENSP00000216237.5

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000880 AC: 22 AN: 250094 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135414

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.0000836 AC: 122 AN: 1460074 Hom.: 0 Cov.: 31 AF XY: 0.0000854 AC XY: 62 AN XY: 726324

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74330

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2282G>A (p.R761H) alteration is located in exon 6 (coding exon 6) of the CHADL gene. This alteration results from a G to A substitution at nucleotide position 2282, causing the arginine (R) at amino acid position 761 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.1
DANN	Benign	0.95
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.063
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0010	B
Vest4		0.085
MVP		0.21
MPC		0.026
ClinPred		0.038	T
GERP RS		0.15
Varity_R		0.031
gMVP		0.38

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

Other links and lift over

dbSNP: rs769398487; hg19: chr22-41625715; COSMIC: COSV53436692; COSMIC: COSV53436692;