rs371826762

Variant names:

• chr2-178709578-T-C
• rs371826762
• NM_001267550.2:c.28741A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.28741A>G​(p.Ile9581Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,605,922 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I9581F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:9
• Conservation: PhyloP100: 0.338
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077707767).
• BP6: Variant 2-178709578-T-C is Benign according to our data. Variant chr2-178709578-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178232.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00018 (262/1453556) while in subpopulation MID AF = 0.00559 (32/5724). AF 95% confidence interval is 0.00407. There are 0 homozygotes in GnomAdExome4. There are 119 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.28741A>G	p.Ile9581Val	missense	Exon 99 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.27790A>G	p.Ile9264Val	missense	Exon 97 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.25009A>G	p.Ile8337Val	missense	Exon 96 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.28741A>G	p.Ile9581Val	missense	Exon 99 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.28741A>G	p.Ile9581Val	missense	Exon 99 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.28465A>G	p.Ile9489Val	missense	Exon 97 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000173 AC: 43 AN: 247902 AF XY: 0.000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000180 AC: 262 AN: 1453556 Hom.: 0 Cov.: 31 AF XY: 0.000165 AC XY: 119 AN XY: 721156

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.000179 AC: 8 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26052

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39496

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00559 AC: 32 AN: 5724

European-Non Finnish (NFE) AF: 0.000118 AC: 130 AN: 1105020

Other (OTH) AF: 0.000333 AC: 20 AN: 60018

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74508

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000219

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	1	2	not provided (3)
-	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	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)
-	-	1	Supraventricular tachycardia (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.4
DANN	Benign	0.65
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.34
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.066
Sift	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.12
MPC		0.071
ClinPred		0.0068	T
GERP RS		-0.83
Mutation Taster		=89/11	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: rs371826762; hg19: chr2-179574305;