rs78535378

chr2-178756545-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):c.10931G>A(p.Ser3644Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,611,698 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 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. S3644S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (186 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.633

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

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015839636).
• BP6: Variant 2-178756545-C-T is Benign according to our data. Variant chr2-178756545-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178756545-C-T is described in Lovd as [Benign]. Variant chr2-178756545-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.10931G>A	p.Ser3644Asn	missense_variant	46/363	ENST00000589042.5
TTN	NM_133379.5	c.10303+2439G>A		intron_variant		ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.10931G>A	p.Ser3644Asn	missense_variant	46/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.10303+2439G>A		intron_variant		5	NM_133379.5
TTN-AS1	ENST00000659121.1	n.1280+223C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 647 AN: 152182 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0622

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00680 AC: 1685 AN: 247868 Hom.: 33 AF XY: 0.00660 AC XY: 887 AN XY: 134454

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000801

Gnomad EAS exome AF: 0.0557

Gnomad SAS exome AF: 0.00214

Gnomad FIN exome AF: 0.0230

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.00583

GnomAD4 exome AF: 0.00373 AC: 5441 AN: 1459398 Hom.: 186 Cov.: 33 AF XY: 0.00377 AC XY: 2734 AN XY: 725658

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000652

Gnomad4 EAS exome AF: 0.0861

Gnomad4 SAS exome AF: 0.00224

Gnomad4 FIN exome AF: 0.0247

Gnomad4 NFE exome AF: 0.000238

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.00424 AC: 646 AN: 152300 Hom.: 13 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74470

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0622

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00286 Hom.: 19

Bravo AF: 0.00252

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000482 AC: 4

ExAC AF: 0.00660 AC: 798

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 21, 2013	Ser3473Asn in exon 44B of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 9.1% (52/572) of Asian chromosomes b y the 1000 Genomes Project (dbSNP rs78535378). -

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 31, 2024

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

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	-0.62	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	15
Dann	Benign	0.93
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
Vest4		0.063
MVP		0.44
MPC		0.078
ClinPred		0.011	T
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs78535378; hg19: chr2-179621272; COSMIC: COSV59895003; COSMIC: COSV59895003;