NM_001267550.2:c.32480C>T

Variant names:

• chr2-178684980-G-A
• rs72650030
• NM_001267550.2:c.32480C>T

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.32480C>T​(p.Ala10827Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,602,160 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 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 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:19
• Conservation: PhyloP100: 0.804
• Publications: 9 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=0.004187286).
• BP6: Variant 2-178684980-G-A is Benign according to our data. Variant chr2-178684980-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46868.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00133 (202/152260) while in subpopulation NFE AF = 0.00251 (171/68002). AF 95% confidence interval is 0.00221. There are 1 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.32480C>T	p.Ala10827Val	missense	Exon 130 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.31529C>T	p.Ala10510Val	missense	Exon 128 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.28748C>T	p.Ala9583Val	missense	Exon 127 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.32480C>T	p.Ala10827Val	missense	Exon 130 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.32480C>T	p.Ala10827Val	missense	Exon 130 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.32204C>T	p.Ala10735Val	missense	Exon 128 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00156 AC: 356 AN: 228620 AF XY: 0.00169

Gnomad AFR exome AF: 0.000222

Gnomad AMR exome AF: 0.000394

Gnomad ASJ exome AF: 0.00128

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000292

Gnomad NFE exome AF: 0.00285

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.00209 AC: 3025 AN: 1449900 Hom.: 5 Cov.: 31 AF XY: 0.00204 AC XY: 1467 AN XY: 720080

African (AFR) AF: 0.000360 AC: 12 AN: 33322

American (AMR) AF: 0.000298 AC: 13 AN: 43606

Ashkenazi Jewish (ASJ) AF: 0.000974 AC: 25 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00101 AC: 85 AN: 84368

European-Finnish (FIN) AF: 0.000190 AC: 10 AN: 52638

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5750

European-Non Finnish (NFE) AF: 0.00252 AC: 2783 AN: 1105106

Other (OTH) AF: 0.00130 AC: 78 AN: 59858

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74444

African (AFR) AF: 0.000361 AC: 15 AN: 41544

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68002

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00234 Hom.: 2

Bravo AF: 0.00137

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000552 AC: 2

ESP6500EA AF: 0.00208 AC: 17

ExAC AF: 0.00145 AC: 174

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	6	not specified (6)
-	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	Cardiomyopathy (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.96
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.80
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.10
Sift	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.062
MVP		0.16
MPC		0.083
ClinPred		0.011	T
GERP RS		2.1
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: rs72650030; hg19: chr2-179549707;