2-178677696-G-T

Variant names:

• chr2-178677696-G-T
• rs532102837
• NM_001267550.2:c.34216C>A

Variant summary

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

The ENST00000589042.5(TTN):​c.34216C>A​(p.Pro11406Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,612,698 control chromosomes in the GnomAD database, including 1 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 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: TTN ENST00000589042.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:10
• Conservation: PhyloP100: 0.626
• Publications: 7 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=0.007362187).
• BP6: Variant 2-178677696-G-T is Benign according to our data. Variant chr2-178677696-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191992.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000151 (23/151938) while in subpopulation EAS AF = 0.00426 (22/5160). AF 95% confidence interval is 0.00289. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. 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.34216C>A	p.Pro11406Thr	missense	Exon 146 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.33265C>A	p.Pro11089Thr	missense	Exon 144 of 313	NP_001243779.1
	TTN	NM_133378.4		c.30484C>A	p.Pro10162Thr	missense	Exon 143 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.34216C>A	p.Pro11406Thr	missense	Exon 146 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.34216C>A	p.Pro11406Thr	missense	Exon 146 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.33940C>A	p.Pro11314Thr	missense	Exon 144 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151820 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000583 AC: 145 AN: 248850 AF XY: 0.000518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00807

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 179 AN: 1460760 Hom.: 1 Cov.: 31 AF XY: 0.000122 AC XY: 89 AN XY: 726652

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00431 AC: 171 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111258

Other (OTH) AF: 0.0000497 AC: 3 AN: 60330

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151938 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74272

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.0000657 AC: 1 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00426 AC: 22 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67900

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000379 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.000463 AC: 56

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	3	not specified (3)
-	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	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.83
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.63
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.096
Sift	Benign	0.73	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.23		Gain of phosphorylation at P11089 (P = 0.0115)
MVP		0.29
MPC		0.093
ClinPred		0.029	T
GERP RS		2.9
Mutation Taster		=95/5	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: rs532102837; hg19: chr2-179542423;