2-178657535-C-T

Position:

• chr2-178657535-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001267550.2(TTN):​c.38001G>A​(p.Ser12667=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,437,016 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (5 hom., cov: 18)
  • Exomes 𝑓: 0.00028 (29 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.759

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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-178657535-C-T is Benign according to our data. Variant chr2-178657535-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 535654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178657535-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.759 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.38001G>A	p.Ser12667=	synonymous_variant	189/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2185+13034C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.38001G>A	p.Ser12667=	synonymous_variant	189/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+59854C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000209 AC: 30 AN: 143676 Hom.: 5 Cov.: 18

Gnomad AFR AF: 0.0000255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000529

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000207

Gnomad SAS AF: 0.000242

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000302

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 36 AN: 238730 Hom.: 5 AF XY: 0.000161 AC XY: 21 AN XY: 130264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000250

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000173

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000280 AC: 402 AN: 1437016 Hom.: 29 Cov.: 31 AF XY: 0.000270 AC XY: 193 AN XY: 714278

Gnomad4 AFR exome AF: 0.0000610

Gnomad4 AMR exome AF: 0.000265

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000774

Gnomad4 SAS exome AF: 0.0000246

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.000506

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000209 AC: 30 AN: 143772 Hom.: 5 Cov.: 18 AF XY: 0.000187 AC XY: 13 AN XY: 69640

Gnomad4 AFR AF: 0.0000254

Gnomad4 AMR AF: 0.000528

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000208

Gnomad4 SAS AF: 0.000243

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000302

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.3
DANN	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201179474; hg19: chr2-179522262;