rs1555604778

Variant names:

• chr17-59660395-TGTCA-T
• rs1555604778
• NM_004859.4:c.977_980delCAGT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004859.4(CLTC):​c.977_980delCAGT​(p.Ser326CysfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S326S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLTC NM_004859.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

CLTC (HGNC:2092): (clathrin heavy chain) Clathrin is a major protein component of the cytoplasmic face of intracellular organelles, called coated vesicles and coated pits. These specialized organelles are involved in the intracellular trafficking of receptors and endocytosis of a variety of macromolecules. The basic subunit of the clathrin coat is composed of three heavy chains and three light chains. [provided by RefSeq, Jul 2008]

CLTC Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 56

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-59660395-TGTCA-T is Pathogenic according to our data. Variant chr17-59660395-TGTCA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 488417.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004859.4. 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
	CLTC	NM_004859.4	MANE Select	c.977_980delCAGT	p.Ser326CysfsTer8	frameshift	Exon 7 of 32	NP_004850.1
	CLTC	NM_001288653.2		c.989_992delCAGT	p.Ser330CysfsTer8	frameshift	Exon 7 of 32	NP_001275582.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLTC	ENST00000269122.8	TSL:1 MANE Select	c.977_980delCAGT	p.Ser326CysfsTer8	frameshift	Exon 7 of 32	ENSP00000269122.3
	CLTC	ENST00000393043.5	TSL:1	c.977_980delCAGT	p.Ser326CysfsTer8	frameshift	Exon 7 of 31	ENSP00000376763.1
	CLTC	ENST00000700714.2		c.977_980delCAGT	p.Ser326CysfsTer8	frameshift	Exon 7 of 34	ENSP00000515154.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, autosomal dominant 56 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1555604778; hg19: chr17-57737756;