2-178751483-G-A

Variant names:

• chr2-178751483-G-A
• rs140804168
• NM_001267550.2:c.11311+1641C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.11311+1641C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,234 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (1 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.144
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 2-178751483-G-A is Benign according to our data. Variant chr2-178751483-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00191 (290/152078) while in subpopulation AMR AF = 0.0084 (128/15246). AF 95% confidence interval is 0.00721. There are 1 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.11311+1641C>T		intron	N/A	NP_001254479.2
	TTN	NM_133379.5		c.10917C>T	p.Gly3639Gly	synonymous	Exon 46 of 46	NP_596870.2
	TTN	NM_001256850.1		c.10360+1641C>T		intron	N/A	NP_001243779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+1641C>T		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11311+1641C>T		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.11035+1641C>T		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 151960 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00841

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00127 AC: 317 AN: 250592 AF XY: 0.00124

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00145 AC: 2120 AN: 1461156 Hom.: 1 Cov.: 39 AF XY: 0.00145 AC XY: 1056 AN XY: 726884

African (AFR) AF: 0.000209 AC: 7 AN: 33442

American (AMR) AF: 0.00365 AC: 163 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53356

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.00164 AC: 1825 AN: 1111578

Other (OTH) AF: 0.00167 AC: 101 AN: 60358

GnomAD4 genome AF: 0.00191 AC: 290 AN: 152078 Hom.: 1 Cov.: 32 AF XY: 0.00217 AC XY: 161 AN XY: 74356

African (AFR) AF: 0.000361 AC: 15 AN: 41534

American (AMR) AF: 0.00840 AC: 128 AN: 15246

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 67906

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00238

EpiCase AF: 0.00202

EpiControl AF: 0.00202

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	not specified (5)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		0.14
Mutation Taster		=82/18	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: rs140804168; hg19: chr2-179616210;