rs55806007

Variant names:

• chr2-178531147-C-T
• rs55806007
• NM_001267550.2:c.105468G>A
• TTN p.Pro35156Pro

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.105468G>A​(p.Pro35156Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00977 in 1,613,934 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (101 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: -2.19
• Publications: 3 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=-0.48).
• BP6: Variant 2-178531147-C-T is Benign according to our data. Variant chr2-178531147-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00798 (1215/152238) while in subpopulation NFE AF = 0.0106 (720/68026). AF 95% confidence interval is 0.00994. There are 6 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.105468G>A	p.Pro35156Pro	synonymous	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.100545G>A	p.Pro33515Pro	synonymous	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.97764G>A	p.Pro32588Pro	synonymous	Exon 307 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.105468G>A	p.Pro35156Pro	synonymous	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.105312G>A	p.Pro35104Pro	synonymous	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.105192G>A	p.Pro35064Pro	synonymous	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1214 AN: 152120 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00891 AC: 2219 AN: 249148 AF XY: 0.00882

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00432

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00995 AC: 14547 AN: 1461696 Hom.: 101 Cov.: 34 AF XY: 0.00987 AC XY: 7180 AN XY: 727134

African (AFR) AF: 0.00134 AC: 45 AN: 33478

American (AMR) AF: 0.00443 AC: 198 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 420 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00694 AC: 599 AN: 86258

European-Finnish (FIN) AF: 0.0157 AC: 838 AN: 53400

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.0106 AC: 11833 AN: 1111860

Other (OTH) AF: 0.00981 AC: 592 AN: 60374

GnomAD4 genome AF: 0.00798 AC: 1215 AN: 152238 Hom.: 6 Cov.: 32 AF XY: 0.00811 AC XY: 604 AN XY: 74442

African (AFR) AF: 0.00226 AC: 94 AN: 41530

American (AMR) AF: 0.00471 AC: 72 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4824

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0106 AC: 720 AN: 68026

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00979 Hom.: 3

Bravo AF: 0.00680

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.00966

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	-0.48
CADD	Benign	0.0020
DANN	Benign	0.93
PhyloP100		-2.2
Mutation Taster		=95/5	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

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

Other links and lift over

dbSNP: rs55806007;

hg19: chr2-179395874;