chr2-178535858-G-A

Variant names:

• chr2-178535858-G-A
• rs77483833
• NM_001267550.2:c.100766-9C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001267550.2(TTN):​c.100766-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 intron
• Scores: Splicing: ADA: 0.001820
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.467
• Publications: 1 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]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-178535858-G-A is Benign according to our data. Variant chr2-178535858-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.100766-9C>T		intron_variant	Intron 357 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.100766-9C>T		intron_variant	Intron 357 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 199 AN: 104304 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00161

Gnomad AMI AF: 0.00332

Gnomad AMR AF: 0.000908

Gnomad ASJ AF: 0.000754

Gnomad EAS AF: 0.000521

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.00969

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0116 AC: 643 AN: 55198 AF XY: 0.0115

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.00962

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00803

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00813

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00220 AC: 2489 AN: 1129796 Hom.: 0 Cov.: 27 AF XY: 0.00253 AC XY: 1403 AN XY: 553568

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00396 AC: 101 AN: 25498

American (AMR) AF: 0.00895 AC: 184 AN: 20568

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 54 AN: 17796

East Asian (EAS) AF: 0.00344 AC: 116 AN: 33748

South Asian (SAS) AF: 0.00938 AC: 517 AN: 55126

European-Finnish (FIN) AF: 0.00579 AC: 194 AN: 33496

Middle Eastern (MID) AF: 0.00652 AC: 27 AN: 4144

European-Non Finnish (NFE) AF: 0.00137 AC: 1218 AN: 891584

Other (OTH) AF: 0.00163 AC: 78 AN: 47836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00192 AC: 200 AN: 104330 Hom.: 0 Cov.: 30 AF XY: 0.00207 AC XY: 103 AN XY: 49684

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00161 AC: 44 AN: 27334

American (AMR) AF: 0.000907 AC: 9 AN: 9924

Ashkenazi Jewish (ASJ) AF: 0.000754 AC: 2 AN: 2654

East Asian (EAS) AF: 0.000522 AC: 2 AN: 3830

South Asian (SAS) AF: 0.00171 AC: 6 AN: 3500

European-Finnish (FIN) AF: 0.00969 AC: 58 AN: 5988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 198

European-Non Finnish (NFE) AF: 0.00155 AC: 76 AN: 48882

Other (OTH) AF: 0.000705 AC: 1 AN: 1418

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00196 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 22, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

93062-9C>T in intron 306 of TTN: This variant is not expected to have clinical s ignificance because it is located outside the conserved +/- 1, 2 region of the s plicing consensus sequence and as part of a poly T stretch. -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Mar 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tibial muscular dystrophy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.054
SpliceAI score (max)		0.020		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: rs77483833; hg19: chr2-179400585;