rs11897366

Variant names:

• chr2-178551829-A-C
• rs11897366
• NM_001267550.2:c.91071T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178551829-A-C
• chr2-178551829-A-G
• chr2-178551829-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.91071T>G​(p.Thr30357Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 1,613,714 control chromosomes in the GnomAD database, including 6,580 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. T30357T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1819 hom., cov: 33)
  • Exomes 𝑓: 0.055 (4761 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.31
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-178551829-A-C is Benign according to our data. Variant chr2-178551829-A-C is described in ClinVar as Benign. ClinVar VariationId is 47504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 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.91071T>G	p.Thr30357Thr	synonymous	Exon 335 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.86148T>G	p.Thr28716Thr	synonymous	Exon 285 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.83367T>G	p.Thr27789Thr	synonymous	Exon 284 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.91071T>G	p.Thr30357Thr	synonymous	Exon 335 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.90915T>G	p.Thr30305Thr	synonymous	Exon 333 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.90795T>G	p.Thr30265Thr	synonymous	Exon 333 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17622 AN: 152022 Hom.: 1797 Cov.: 33

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0934

GnomAD2 exomes AF: 0.0939 AC: 23329 AN: 248474 AF XY: 0.0892

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0276

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0708

GnomAD4 exome AF: 0.0553 AC: 80789 AN: 1461574 Hom.: 4761 Cov.: 34 AF XY: 0.0571 AC XY: 41545 AN XY: 727060

African (AFR) AF: 0.270 AC: 9052 AN: 33468

American (AMR) AF: 0.206 AC: 9204 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 948 AN: 26128

East Asian (EAS) AF: 0.0138 AC: 547 AN: 39694

South Asian (SAS) AF: 0.175 AC: 15067 AN: 86254

European-Finnish (FIN) AF: 0.0593 AC: 3166 AN: 53400

Middle Eastern (MID) AF: 0.0604 AC: 348 AN: 5762

European-Non Finnish (NFE) AF: 0.0345 AC: 38356 AN: 1111778

Other (OTH) AF: 0.0679 AC: 4101 AN: 60370

GnomAD4 genome AF: 0.116 AC: 17696 AN: 152140 Hom.: 1819 Cov.: 33 AF XY: 0.121 AC XY: 9010 AN XY: 74378

African (AFR) AF: 0.258 AC: 10682 AN: 41468

American (AMR) AF: 0.178 AC: 2725 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3470

East Asian (EAS) AF: 0.0251 AC: 130 AN: 5174

South Asian (SAS) AF: 0.177 AC: 853 AN: 4814

European-Finnish (FIN) AF: 0.0585 AC: 620 AN: 10602

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2295 AN: 68018

Other (OTH) AF: 0.0924 AC: 195 AN: 2110

Alfa AF: 0.0644 Hom.: 1110

Bravo AF: 0.129

Asia WGS AF: 0.130 AC: 450 AN: 3476

EpiCase AF: 0.0334

EpiControl AF: 0.0346

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.15
DANN	Benign	0.67
PhyloP100		1.3
Mutation Taster		=90/10	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: rs11897366; hg19: chr2-179416556; COSMIC: COSV60092319; COSMIC: COSV60092319;