chr2-178723552-C-T

Variant names:

• chr2-178723552-C-T
• rs189951108
• NM_001267550.2:c.21548G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.21548G>A​(p.Cys7183Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,613,390 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:8
• Conservation: PhyloP100: 3.41
• Publications: 10 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]

ENSG00000267784 (HGNC:):

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07189745).
• BP6: Variant 2-178723552-C-T is Benign according to our data. Variant chr2-178723552-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178242.

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.21548G>A	p.Cys7183Tyr	missense	Exon 74 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.20597G>A	p.Cys6866Tyr	missense	Exon 72 of 313	NP_001243779.1
	TTN	NM_133378.4		c.17816G>A	p.Cys5939Tyr	missense	Exon 71 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.21548G>A	p.Cys7183Tyr	missense	Exon 74 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.21548G>A	p.Cys7183Tyr	missense	Exon 74 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.21272G>A	p.Cys7091Tyr	missense	Exon 72 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000415 AC: 103 AN: 248348 AF XY: 0.000475

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000494

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000658

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000747 AC: 1092 AN: 1461162 Hom.: 1 Cov.: 33 AF XY: 0.000729 AC XY: 530 AN XY: 726840

African (AFR) AF: 0.0000897 AC: 3 AN: 33450

American (AMR) AF: 0.000604 AC: 27 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000905 AC: 1006 AN: 1111596

Other (OTH) AF: 0.000398 AC: 24 AN: 60332

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74426

African (AFR) AF: 0.000120 AC: 5 AN: 41558

American (AMR) AF: 0.000393 AC: 6 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000883 AC: 60 AN: 67988

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000684 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00122 AC: 10

ExAC AF: 0.000348 AC: 42

EpiCase AF: 0.000982

EpiControl AF: 0.000831

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	3	not provided (10)
-	1	2	not specified (3)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Skeletal dysplasia (1)
-	1	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.95
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.42	T
PhyloP100		3.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.34
Sift	Benign	1.0	T
Polyphen		1.0	D
Vest4		0.53
MVP		0.74
MPC		0.59
ClinPred		0.085	T
GERP RS		6.2
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs189951108; hg19: chr2-179588279; COSMIC: COSV60071970;