chr22-19183443-C-G

Position:

• chr22-19183443-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007098.4(CLTCL1):​c.4774G>C​(p.Val1592Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,658 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1592M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (9 hom.)
• Consequence: CLTCL1 NM_007098.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00200

Genes affected

CLTCL1 (HGNC:2093): (clathrin heavy chain like 1) This gene is a member of the clathrin heavy chain family and encodes a major protein of the polyhedral coat of coated pits and vesicles. Chromosomal aberrations involving this gene are associated with meningioma, DiGeorge syndrome, and velo-cardio-facial syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003834635).
• BP6: Variant 22-19183443-C-G is Benign according to our data. Variant chr22-19183443-C-G is described in ClinVar as [Benign]. Clinvar id is 716364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00676 (1030/152328) while in subpopulation AFR AF= 0.0233 (967/41560). AF 95% confidence interval is 0.0221. There are 12 homozygotes in gnomad4. There are 470 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLTCL1	NM_007098.4	c.4774G>C	p.Val1592Leu	missense_variant	30/33	ENST00000427926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLTCL1	ENST00000427926.6	c.4774G>C	p.Val1592Leu	missense_variant	30/33	1	NM_007098.4	P1

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 1018 AN: 152210 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

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: 0.0000588

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00189 AC: 469 AN: 248308 Hom.: 6 AF XY: 0.00145 AC XY: 196 AN XY: 134828

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00174

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: 0.000107

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.000743 AC: 1086 AN: 1461330 Hom.: 9 Cov.: 31 AF XY: 0.000637 AC XY: 463 AN XY: 726938

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00676 AC: 1030 AN: 152328 Hom.: 12 Cov.: 33 AF XY: 0.00631 AC XY: 470 AN XY: 74480

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.000230 Hom.: 3

Bravo AF: 0.00802

ExAC AF: 0.00219 AC: 266

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.19
DANN	Benign	0.40
DEOGEN2	Benign	0.051	.;T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.94	D;D;D;D
MetaRNN	Benign	0.0038	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.66	.;N;.;.
MutationTaster	Benign	0.73	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.070	.;N;.;.
REVEL	Benign	0.014
Sift	Benign	0.41	.;T;.;.
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.17
MutPred		0.32		.;Loss of catalytic residue at V1592 (P = 0.0059);.;.;
MVP		0.16
ClinPred		0.00099	T
GERP RS		-6.2
Varity_R		0.038
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs2073738; hg19: chr22-19170956;