NM_001267550.2:c.70830C>T

Variant names:

• chr2-178575302-G-A
• rs12464787
• NM_001267550.2:c.70830C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.70830C>T​(p.Ser23610Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,078 control chromosomes in the GnomAD database, including 66,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4763 hom., cov: 32)
  • Exomes 𝑓: 0.28 (62133 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 1.11
• Publications: 31 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-178575302-G-A is Benign according to our data. Variant chr2-178575302-G-A is described in ClinVar as Benign. ClinVar VariationId is 47293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 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.70830C>T	p.Ser23610Ser	synonymous	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.65907C>T	p.Ser21969Ser	synonymous	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.63126C>T	p.Ser21042Ser	synonymous	Exon 275 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.70830C>T	p.Ser23610Ser	synonymous	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.70674C>T	p.Ser23558Ser	synonymous	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.70554C>T	p.Ser23518Ser	synonymous	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35089 AN: 151896 Hom.: 4765 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.236 AC: 58562 AN: 248000 AF XY: 0.241

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.0451

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.283 AC: 414192 AN: 1461064 Hom.: 62133 Cov.: 55 AF XY: 0.282 AC XY: 204836 AN XY: 726796

African (AFR) AF: 0.116 AC: 3897 AN: 33462

American (AMR) AF: 0.115 AC: 5126 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 5156 AN: 26122

East Asian (EAS) AF: 0.0495 AC: 1955 AN: 39532

South Asian (SAS) AF: 0.215 AC: 18585 AN: 86250

European-Finnish (FIN) AF: 0.377 AC: 20118 AN: 53372

Middle Eastern (MID) AF: 0.207 AC: 1190 AN: 5762

European-Non Finnish (NFE) AF: 0.308 AC: 342597 AN: 1111532

Other (OTH) AF: 0.258 AC: 15568 AN: 60338

GnomAD4 genome AF: 0.231 AC: 35077 AN: 152014 Hom.: 4763 Cov.: 32 AF XY: 0.230 AC XY: 17049 AN XY: 74266

African (AFR) AF: 0.122 AC: 5060 AN: 41510

American (AMR) AF: 0.158 AC: 2410 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3470

East Asian (EAS) AF: 0.0510 AC: 263 AN: 5154

South Asian (SAS) AF: 0.216 AC: 1043 AN: 4818

European-Finnish (FIN) AF: 0.385 AC: 4071 AN: 10562

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20836 AN: 67918

Other (OTH) AF: 0.208 AC: 438 AN: 2104

Alfa AF: 0.268 Hom.: 12956

Bravo AF: 0.204

Asia WGS AF: 0.125 AC: 436 AN: 3478

EpiCase AF: 0.291

EpiControl AF: 0.282

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.16
DANN	Benign	0.81
PhyloP100		1.1
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12464787; hg19: chr2-179440029; COSMIC: COSV59946171; COSMIC: COSV59946171;