rs7224631

Variant names:

• chr17-59655553-G-A
• rs7224631
• NM_004859.4:c.796-301G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004859.4(CLTC):​c.796-301G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 152,114 control chromosomes in the GnomAD database, including 3,371 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3371 hom., cov: 33)
• Consequence: CLTC NM_004859.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTC	NM_004859.4	c.796-301G>A		intron_variant	Intron 5 of 31	ENST00000269122.8	NP_004850.1
CLTC	NM_001288653.2	c.808-301G>A		intron_variant	Intron 5 of 31		NP_001275582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLTC	ENST00000269122.8	c.796-301G>A		intron_variant	Intron 5 of 31	1	NM_004859.4	ENSP00000269122.3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27480 AN: 151996 Hom.: 3357 Cov.: 33

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0973

Gnomad OTH AF: 0.159

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

GnomAD4 genome AF: 0.181 AC: 27523 AN: 152114 Hom.: 3371 Cov.: 33 AF XY: 0.186 AC XY: 13814 AN XY: 74358

African (AFR) AF: 0.286 AC: 11856 AN: 41478

American (AMR) AF: 0.165 AC: 2517 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3470

East Asian (EAS) AF: 0.453 AC: 2345 AN: 5176

South Asian (SAS) AF: 0.381 AC: 1835 AN: 4818

European-Finnish (FIN) AF: 0.129 AC: 1367 AN: 10582

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0973 AC: 6616 AN: 67984

Other (OTH) AF: 0.169 AC: 356 AN: 2112

Alfa AF: 0.133 Hom.: 981

Bravo AF: 0.182

Asia WGS AF: 0.420 AC: 1462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.1
DANN	Benign	0.72
PhyloP100		-0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs7224631; hg19: chr17-57732914;