rs146057575

Variant names:

• chr2-178713986-T-C
• rs146057575
• NM_001267550.2:c.26672A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.26672A>G​(p.Asn8891Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,613,684 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (5 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:15
• Conservation: PhyloP100: 2.54
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010567844).
• BP6: Variant 2-178713986-T-C is Benign according to our data. Variant chr2-178713986-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46785.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000254 (371/1461372) while in subpopulation MID AF = 0.0144 (83/5768). AF 95% confidence interval is 0.0119. There are 5 homozygotes in GnomAdExome4. There are 190 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.26672A>G	p.Asn8891Ser	missense	Exon 92 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.25721A>G	p.Asn8574Ser	missense	Exon 90 of 313	NP_001243779.1
	TTN	NM_133378.4		c.22940A>G	p.Asn7647Ser	missense	Exon 89 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.26672A>G	p.Asn8891Ser	missense	Exon 92 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.26672A>G	p.Asn8891Ser	missense	Exon 92 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.26396A>G	p.Asn8799Ser	missense	Exon 90 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000366 AC: 91 AN: 248780 AF XY: 0.000407

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000254 AC: 371 AN: 1461372 Hom.: 5 Cov.: 31 AF XY: 0.000261 AC XY: 190 AN XY: 726948

African (AFR) AF: 0.000568 AC: 19 AN: 33460

American (AMR) AF: 0.000626 AC: 28 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5768

European-Non Finnish (NFE) AF: 0.000153 AC: 170 AN: 1111672

Other (OTH) AF: 0.000447 AC: 27 AN: 60354

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74470

African (AFR) AF: 0.000192 AC: 8 AN: 41584

American (AMR) AF: 0.00118 AC: 18 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000389 Hom.: 0

Bravo AF: 0.000393

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000348 AC: 42

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000534

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	7	not provided (9)
-	-	4	not specified (4)
-	-	2	Tibial muscular dystrophy (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.48
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.089
Sift	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.059
MVP		0.048
MPC		0.067
ClinPred		0.0094	T
GERP RS		-0.95
Mutation Taster		=96/4	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: rs146057575; hg19: chr2-179578713;