rs78535378

Variant names:

• chr2-178756545-C-T
• rs78535378
• NM_001267550.2:c.10931G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 13/16 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:11
• Conservation: PhyloP100: 0.633
• Publications: 11 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 -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 137833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.10931G>A	p.Ser3644Asn	missense	Exon 46 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_133437.4		c.10418G>A	p.Ser3473Asn	missense	Exon 44 of 192	NP_597681.4	A0A0A0MRA3
	TTN	NM_001256850.1		c.10303+2439G>A		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.10931G>A	p.Ser3644Asn	missense	Exon 46 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.10931G>A	p.Ser3644Asn	missense	Exon 46 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.10655G>A	p.Ser3552Asn	missense	Exon 44 of 361	ENSP00000405517.2	A0A0C4DG59

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

GnomAD2 exomes AF: 0.00680 AC: 1685 AN: 247868 AF XY: 0.00660

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 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

African (AFR) AF: 0.000210 AC: 7 AN: 33366

American (AMR) AF: 0.000157 AC: 7 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.000652 AC: 17 AN: 26072

East Asian (EAS) AF: 0.0861 AC: 3413 AN: 39636

South Asian (SAS) AF: 0.00224 AC: 193 AN: 86122

European-Finnish (FIN) AF: 0.0247 AC: 1318 AN: 53318

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5752

European-Non Finnish (NFE) AF: 0.000238 AC: 264 AN: 1110264

Other (OTH) AF: 0.00352 AC: 212 AN: 60280

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41574

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0622 AC: 322 AN: 5178

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.0235 AC: 250 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00276 Hom.: 45

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.63
PROVEAN	Benign	0.16	N
REVEL	Benign	0.11
Sift	Benign	0.64	T
Vest4		0.063
MVP		0.44
MPC		0.078
ClinPred		0.011	T
GERP RS		4.6
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs78535378; hg19: chr2-179621272; COSMIC: COSV59895003; COSMIC: COSV59895003;