2-178704673-C-T

Variant names:

• chr2-178704673-C-T
• rs2742344
• NM_001267550.2:c.29799G>A
• TTN p.Ser9933Ser

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.29799G>A​(p.Ser9933Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,611,548 control chromosomes in the GnomAD database, including 1,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S9933S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.051 (315 hom., cov: 33)
  • Exomes 𝑓: 0.032 (1489 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.308
• Publications: 9 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 2-178704673-C-T is Benign according to our data. Variant chr2-178704673-C-T is described in ClinVar as Benign. ClinVar VariationId is 46825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.308 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 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.29799G>A	p.Ser9933Ser	synonymous	Exon 105 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.28848G>A	p.Ser9616Ser	synonymous	Exon 103 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26067G>A	p.Ser8689Ser	synonymous	Exon 102 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.29799G>A	p.Ser9933Ser	synonymous	Exon 105 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.29799G>A	p.Ser9933Ser	synonymous	Exon 105 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.29523G>A	p.Ser9841Ser	synonymous	Exon 103 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7814 AN: 152066 Hom.: 316 Cov.: 33

Gnomad AFR AF: 0.0853

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0488

GnomAD2 exomes AF: 0.0489 AC: 11940 AN: 244304 AF XY: 0.0453

Gnomad AFR exome AF: 0.0884

Gnomad AMR exome AF: 0.0463

Gnomad ASJ exome AF: 0.0320

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.0502

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0387

GnomAD4 exome AF: 0.0323 AC: 47187 AN: 1459364 Hom.: 1489 Cov.: 32 AF XY: 0.0320 AC XY: 23222 AN XY: 725830

African (AFR) AF: 0.0837 AC: 2802 AN: 33464

American (AMR) AF: 0.0448 AC: 1990 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 848 AN: 26064

East Asian (EAS) AF: 0.190 AC: 7541 AN: 39656

South Asian (SAS) AF: 0.0307 AC: 2637 AN: 86036

European-Finnish (FIN) AF: 0.0520 AC: 2756 AN: 52986

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5762

European-Non Finnish (NFE) AF: 0.0236 AC: 26249 AN: 1110702

Other (OTH) AF: 0.0373 AC: 2250 AN: 60278

GnomAD4 genome AF: 0.0514 AC: 7815 AN: 152184 Hom.: 315 Cov.: 33 AF XY: 0.0518 AC XY: 3851 AN XY: 74396

African (AFR) AF: 0.0851 AC: 3532 AN: 41490

American (AMR) AF: 0.0388 AC: 594 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3468

East Asian (EAS) AF: 0.191 AC: 989 AN: 5180

South Asian (SAS) AF: 0.0365 AC: 176 AN: 4828

European-Finnish (FIN) AF: 0.0490 AC: 519 AN: 10598

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0257 AC: 1745 AN: 68008

Other (OTH) AF: 0.0473 AC: 100 AN: 2114

Alfa AF: 0.0326 Hom.: 163

Bravo AF: 0.0538

Asia WGS AF: 0.0850 AC: 294 AN: 3478

ClinVar

ClinVar submissions

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	-0.28
CADD	Benign	3.9
DANN	Benign	0.73
PhyloP100		-0.31
Mutation Taster		=81/19	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2742344;

hg19: chr2-179569400;

COSMIC: COSV59946363;

COSMIC: COSV59946363;