chr2-55181606-C-T

Variant names:

• chr2-55181606-C-T
• rs144133542
• NM_152385.4:c.1145G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_152385.4(CLHC1):​c.1145G>A​(p.Arg382Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,612,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R382W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CLHC1 NM_152385.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.28
• Publications: 3 publications found

Genes affected

CLHC1 (HGNC:26453): (clathrin heavy chain linker domain containing 1)

ACMG classification

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

• PP5: Variant 2-55181606-C-T is Pathogenic according to our data. Variant chr2-55181606-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183280.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.021851927). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152385.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLHC1	NM_152385.4	MANE Select	c.1145G>A	p.Arg382Gln	missense	Exon 10 of 13	NP_689598.2
	CLHC1	NM_001353780.2		c.947G>A	p.Arg316Gln	missense	Exon 8 of 11	NP_001340709.1
	CLHC1	NM_001135598.2		c.779G>A	p.Arg260Gln	missense	Exon 8 of 11	NP_001129070.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLHC1	ENST00000401408.6	TSL:1 MANE Select	c.1145G>A	p.Arg382Gln	missense	Exon 10 of 13	ENSP00000384869.1
	CLHC1	ENST00000406076.5	TSL:1	c.779G>A	p.Arg260Gln	missense	Exon 8 of 11	ENSP00000385512.1
	CLHC1	ENST00000407122.5	TSL:5	c.1145G>A	p.Arg382Gln	missense	Exon 9 of 12	ENSP00000385778.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000268 AC: 67 AN: 249746 AF XY: 0.000163

Gnomad AFR exome AF: 0.00407

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000175 AC: 255 AN: 1460018 Hom.: 0 Cov.: 30 AF XY: 0.000154 AC XY: 112 AN XY: 726230

African (AFR) AF: 0.00444 AC: 148 AN: 33364

American (AMR) AF: 0.0000678 AC: 3 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85748

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111494

Other (OTH) AF: 0.000199 AC: 12 AN: 60318

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74416

African (AFR) AF: 0.00477 AC: 198 AN: 41524

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000389 Hom.: 1

Bravo AF: 0.00141

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Waddling gait;CN228301:Marked Hypotonia Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.053	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		2.3
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.37
MPC		0.031
ClinPred		0.26	T
GERP RS		5.8
Varity_R		0.36
gMVP		0.46
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs144133542; hg19: chr2-55408742; COSMIC: COSV107509107;