rs370765948

Positions:

• chr2-178661797-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001267550.2(TTN):​c.37247C>T​(p.Ser12416Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S12416S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 18)
  • Exomes 𝑓: 0.0014 (36 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.41

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.011146307).
• BP6: Variant 2-178661797-G-A is Benign according to our data. Variant chr2-178661797-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 192171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178661797-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.37247C>T	p.Ser12416Leu	missense_variant	180/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+17296G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.37247C>T	p.Ser12416Leu	missense_variant	180/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+64116G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 290 AN: 149962 Hom.: 4 Cov.: 18

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00276

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00258

Gnomad OTH AF: 0.000971

GnomAD3 exomes AF: 0.000999 AC: 245 AN: 245308 Hom.: 4 AF XY: 0.000920 AC XY: 123 AN XY: 133736

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000494

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.000560

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00150

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00138 AC: 2013 AN: 1456722 Hom.: 36 Cov.: 31 AF XY: 0.00145 AC XY: 1051 AN XY: 724654

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.000650

Gnomad4 ASJ exome AF: 0.000767

Gnomad4 EAS exome AF: 0.000530

Gnomad4 SAS exome AF: 0.000372

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00152

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00195 AC: 292 AN: 150078 Hom.: 5 Cov.: 18 AF XY: 0.00183 AC XY: 134 AN XY: 73312

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00178

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000977

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.00276

Gnomad4 NFE AF: 0.00258

Gnomad4 OTH AF: 0.000961

Alfa AF: 0.00191 Hom.: 1

ESP6500AA AF: 0.00402 AC: 7

ESP6500EA AF: 0.000502 AC: 2

ExAC AF: 0.00124 AC: 149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TTN: BP4, BS2 -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.013
DANN	Benign	0.43
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
Vest4		0.047
MVP		0.15
MPC		0.074
ClinPred		0.0026	T
GERP RS		-5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs370765948; hg19: chr2-179526524;