chr2-178650771-G-A

Variant names:

• chr2-178650771-G-A
• rs148140756
• NM_001267550.2:c.39689C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.39689C>T​(p.Ala13230Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,606,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A13230A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:10
• Conservation: PhyloP100: -0.246
• Publications: 8 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005412787).
• BP6: Variant 2-178650771-G-A is Benign according to our data. Variant chr2-178650771-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166080.

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.39689C>T	p.Ala13230Val	missense	Exon 209 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.35168C>T	p.Ala11723Val	missense	Exon 164 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.32387C>T	p.Ala10796Val	missense	Exon 163 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.39689C>T	p.Ala13230Val	missense	Exon 209 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.39689C>T	p.Ala13230Val	missense	Exon 209 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.39413C>T	p.Ala13138Val	missense	Exon 207 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000503 AC: 120 AN: 238506 AF XY: 0.000403

Gnomad AFR exome AF: 0.000206

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000578

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000575

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.00102 AC: 1489 AN: 1454304 Hom.: 0 Cov.: 31 AF XY: 0.000958 AC XY: 692 AN XY: 722594

African (AFR) AF: 0.000240 AC: 8 AN: 33352

American (AMR) AF: 0.00125 AC: 55 AN: 43940

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39336

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53020

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00117 AC: 1301 AN: 1108410

Other (OTH) AF: 0.00200 AC: 120 AN: 60048

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74460

African (AFR) AF: 0.000313 AC: 13 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000746 Hom.: 1

Bravo AF: 0.000623

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00208 AC: 17

ExAC AF: 0.000489 AC: 59

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	not specified (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	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.28
DANN	Benign	0.73
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.25
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.087
Sift	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.078
MVP		0.048
MPC		0.083
ClinPred		0.0024	T
GERP RS		-3.3
Mutation Taster		=93/7	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: rs148140756; hg19: chr2-179515498;