NM_152385.4:c.1145G>T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_152385.4(CLHC1):​c.1145G>T​(p.Arg382Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R382Q) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CLHC1 NM_152385.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28
• Publications: 3 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

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>T	p.Arg382Leu	missense	Exon 10 of 13	NP_689598.2
	CLHC1	NM_001353780.2		c.947G>T	p.Arg316Leu	missense	Exon 8 of 11	NP_001340709.1
	CLHC1	NM_001135598.2		c.779G>T	p.Arg260Leu	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>T	p.Arg382Leu	missense	Exon 10 of 13	ENSP00000384869.1
	CLHC1	ENST00000406076.5	TSL:1	c.779G>T	p.Arg260Leu	missense	Exon 8 of 11	ENSP00000385512.1
	CLHC1	ENST00000407122.5	TSL:5	c.1145G>T	p.Arg382Leu	missense	Exon 9 of 12	ENSP00000385778.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		2.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.72		Loss of ubiquitination at K381 (P = 0.1016)
MVP		0.45
MPC		0.053
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.45
gMVP		0.62
Mutation Taster		=55/45	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: rs144133542; hg19: chr2-55408742;