chr2-178554639-T-C

Variant names:

• chr2-178554639-T-C
• rs139506970
• NM_001267550.2:c.88708A>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.88708A>G​(p.Ile29570Val) variant causes a missense change. The variant allele was found at a frequency of 0.000501 in 1,613,860 control chromosomes in the GnomAD database, including 9 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I29570L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (6 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 3.95
• Publications: 4 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]

ENSG00000279598 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.006224215).
• BP6: Variant 2-178554639-T-C is Benign according to our data. Variant chr2-178554639-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96313.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00243 (370/152220) while in subpopulation AFR AF = 0.00826 (343/41544). AF 95% confidence interval is 0.00754. There are 3 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.88708A>G	p.Ile29570Val	missense	Exon 332 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.83785A>G	p.Ile27929Val	missense	Exon 282 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.81004A>G	p.Ile27002Val	missense	Exon 281 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.88708A>G	p.Ile29570Val	missense	Exon 332 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.88552A>G	p.Ile29518Val	missense	Exon 330 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.88432A>G	p.Ile29478Val	missense	Exon 330 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152102 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00828

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000607 AC: 151 AN: 248686 AF XY: 0.000512

Gnomad AFR exome AF: 0.00846

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000300 AC: 438 AN: 1461640 Hom.: 6 Cov.: 32 AF XY: 0.000312 AC XY: 227 AN XY: 727106

African (AFR) AF: 0.00869 AC: 291 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1111822

Other (OTH) AF: 0.000812 AC: 49 AN: 60370

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152220 Hom.: 3 Cov.: 33 AF XY: 0.00253 AC XY: 188 AN XY: 74436

African (AFR) AF: 0.00826 AC: 343 AN: 41544

American (AMR) AF: 0.000850 AC: 13 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68006

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

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.00268

ESP6500AA AF: 0.00636 AC: 26

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000753 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (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	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.91
Eigen	Benign	-0.20
Eigen_PC	Benign	0.0087
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.040	N
PhyloP100		3.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.041
Sift	Benign	0.12	T
Polyphen		0.020	B
Vest4		0.12
MVP		0.39
MPC		0.078
ClinPred		0.012	T
GERP RS		4.5
Mutation Taster		=86/14	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: rs139506970; hg19: chr2-179419366;