rs55956577

Variant names:

• chr2-178595706-G-A
• rs55956577
• NM_001267550.2:c.57648C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.57648C>T​(p.Ile19216Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.00218 in 1,608,760 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (47 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 4.03
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-178595706-G-A is Benign according to our data. Variant chr2-178595706-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00181 (275/152144) while in subpopulation SAS AF = 0.024 (116/4824). AF 95% confidence interval is 0.0205. There are 5 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.57648C>T	p.Ile19216Ile	synonymous	Exon 295 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.52725C>T	p.Ile17575Ile	synonymous	Exon 245 of 313	NP_001243779.1
	TTN	NM_133378.4		c.49944C>T	p.Ile16648Ile	synonymous	Exon 244 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.57648C>T	p.Ile19216Ile	synonymous	Exon 295 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.57492C>T	p.Ile19164Ile	synonymous	Exon 293 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.57372C>T	p.Ile19124Ile	synonymous	Exon 293 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152026 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00362 AC: 870 AN: 240180 AF XY: 0.00459

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.000772

Gnomad ASJ exome AF: 0.000915

Gnomad EAS exome AF: 0.0000582

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00357

GnomAD4 exome AF: 0.00222 AC: 3230 AN: 1456616 Hom.: 47 Cov.: 34 AF XY: 0.00282 AC XY: 2040 AN XY: 723870

African (AFR) AF: 0.000419 AC: 14 AN: 33414

American (AMR) AF: 0.000701 AC: 31 AN: 44196

Ashkenazi Jewish (ASJ) AF: 0.000846 AC: 22 AN: 25994

East Asian (EAS) AF: 0.000178 AC: 7 AN: 39300

South Asian (SAS) AF: 0.0210 AC: 1782 AN: 84920

European-Finnish (FIN) AF: 0.0000753 AC: 4 AN: 53144

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5764

European-Non Finnish (NFE) AF: 0.00105 AC: 1165 AN: 1109662

Other (OTH) AF: 0.00299 AC: 180 AN: 60222

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152144 Hom.: 5 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74358

African (AFR) AF: 0.000241 AC: 10 AN: 41520

American (AMR) AF: 0.00183 AC: 28 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 67982

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00105

Asia WGS AF: 0.0130 AC: 45 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	4.7
DANN	Benign	0.76
PhyloP100		4.0
Mutation Taster		=57/43	polymorphism

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: rs55956577; hg19: chr2-179460433; COSMIC: COSV60186035; COSMIC: COSV60186035;