chr2-178815494-T-C

Variant names:

• chr2-178815494-T-C
• rs2029395
• ENST00000412264.2:c.-14+2032A>G

Variant summary

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

The ENST00000412264.2(TTN):​c.-14+2032A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 152,112 control chromosomes in the GnomAD database, including 8,475 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 0.28 (8475 hom., cov: 32)
• Consequence: TTN ENST00000412264.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 7 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

CCDC141 (HGNC:26821): (coiled-coil domain containing 141) Predicted to be involved in axon guidance and cell adhesion. Predicted to act upstream of or within centrosome localization and cerebral cortex radially oriented cell migration. Predicted to be located in centrosome; cytoplasm; and plasma membrane. Predicted to be active in neuron projection. [provided by Alliance of Genome Resources, Apr 2022]

CCDC141 Gene-Disease associations (from GenCC):

• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC141	XM_047443985.1	c.*432-392A>G		intron_variant	Intron 28 of 28		XP_047299941.1
CCDC141	XM_047443986.1	c.*579-392A>G		intron_variant	Intron 29 of 29		XP_047299942.1
CCDC141	XM_047443988.1	c.*607-392A>G		intron_variant	Intron 28 of 28		XP_047299944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000412264.2	c.-14+2032A>G		intron_variant	Intron 3 of 364	3		ENSP00000394672.2

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41803 AN: 151994 Hom.: 8445 Cov.: 32

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.234

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

GnomAD4 genome AF: 0.275 AC: 41899 AN: 152112 Hom.: 8475 Cov.: 32 AF XY: 0.284 AC XY: 21155 AN XY: 74382

African (AFR) AF: 0.460 AC: 19054 AN: 41464

American (AMR) AF: 0.413 AC: 6306 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3470

East Asian (EAS) AF: 0.785 AC: 4059 AN: 5172

South Asian (SAS) AF: 0.417 AC: 2006 AN: 4816

European-Finnish (FIN) AF: 0.152 AC: 1609 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7741 AN: 67986

Other (OTH) AF: 0.237 AC: 501 AN: 2112

Alfa AF: 0.180 Hom.: 5428

Bravo AF: 0.310

Asia WGS AF: 0.603 AC: 2095 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.18
DANN	Benign	0.52
PhyloP100		-1.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2029395; hg19: chr2-179680221;