chr2-178776385-C-A

Variant names:

• chr2-178776385-C-A
• rs141213991
• NM_001267550.2:c.5479G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.5479G>T​(p.Ala1827Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00127 in 1,612,876 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. A1827T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:17 O:1
• Conservation: PhyloP100: 6.14
• Publications: 12 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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02092442).
• BP6: Variant 2-178776385-C-A is Benign according to our data. Variant chr2-178776385-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47184.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.5479G>T	p.Ala1827Ser	missense	Exon 28 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.5479G>T	p.Ala1827Ser	missense	Exon 28 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.5479G>T	p.Ala1827Ser	missense	Exon 28 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.5479G>T	p.Ala1827Ser	missense	Exon 28 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.5479G>T	p.Ala1827Ser	missense	Exon 28 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.5203G>T	p.Ala1735Ser	missense	Exon 26 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000870 AC: 218 AN: 250448 AF XY: 0.000775

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000478

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00131 AC: 1918 AN: 1460604 Hom.: 2 Cov.: 33 AF XY: 0.00128 AC XY: 933 AN XY: 726662

African (AFR) AF: 0.000299 AC: 10 AN: 33468

American (AMR) AF: 0.00136 AC: 61 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.0000383 AC: 2 AN: 52234

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00159 AC: 1767 AN: 1111954

Other (OTH) AF: 0.00106 AC: 64 AN: 60388

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74466

African (AFR) AF: 0.000241 AC: 10 AN: 41562

American (AMR) AF: 0.00124 AC: 19 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68010

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.00101

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.00115

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	8	not provided (10)
-	-	4	not specified (4)
-	1	1	TTN-related disorder (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Primary dilated cardiomyopathy;C0018801:Heart failure (1)
-	-	-	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.94
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.37	T
PhyloP100		6.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.25
Sift	Benign	0.087	T
Sift4G	Uncertain	0.011	D
Polyphen		0.92	P
Vest4		0.42
MVP		0.28
MPC		0.21
ClinPred		0.035	T
GERP RS		5.2
Mutation Taster		=70/30	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: rs141213991; hg19: chr2-179641112;