22-41229711-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138481.2(CHADL):​c.2282G>T​(p.Arg761Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R761H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHADL NM_138481.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.727
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08894655).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138481.2. 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
	CHADL	NM_138481.2	MANE Select	c.2282G>T	p.Arg761Leu	missense	Exon 6 of 6	NP_612490.1	Q6NUI6-1
	L3MBTL2	NM_031488.5	MANE Select	c.2005+55C>A		intron	N/A	NP_113676.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHADL	ENST00000216241.14	TSL:1 MANE Select	c.2282G>T	p.Arg761Leu	missense	Exon 6 of 6	ENSP00000216241.9	Q6NUI6-1
	L3MBTL2	ENST00000216237.10	TSL:1 MANE Select	c.2005+55C>A		intron	N/A	ENSP00000216237.5	Q969R5-1
	L3MBTL2	ENST00000466589.5	TSL:1	n.2539+55C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250094 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460076 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726324

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4424

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111910

Other (OTH) AF: 0.0000166 AC: 1 AN: 60230

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.5
DANN	Benign	0.89
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.73
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.060
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.037	D
Polyphen		0.18	B
Vest4		0.23
MutPred		0.49		Loss of MoRF binding (P = 5e-04)
MVP		0.20
MPC		0.026
ClinPred		0.17	T
GERP RS		0.15
Varity_R		0.061
gMVP		0.46
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs769398487; hg19: chr22-41625715;