2-55175913-A-C

Position:

• chr2-55175913-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152385.4(CLHC1):​c.1638T>G​(p.Cys546Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,704 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CLHC1 NM_152385.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

Genes affected

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

CLHC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLHC1	NM_152385.4	c.1638T>G	p.Cys546Trp	missense_variant	13/13	ENST00000401408.6	NP_689598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLHC1	ENST00000401408.6	c.1638T>G	p.Cys546Trp	missense_variant	13/13	1	NM_152385.4	ENSP00000384869.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251204 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135760

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461704 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.1638T>G (p.C546W) alteration is located in exon 13 (coding exon 11) of the CLHC1 gene. This alteration results from a T to G substitution at nucleotide position 1638, causing the cysteine (C) at amino acid position 546 to be replaced by a tryptophan (W). 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	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.72	.;T;T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.82
MVP		0.29
MPC		0.055
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.91
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs772844778; hg19: chr2-55403049;