2-178549838-T-A

Variant names:

• chr2-178549838-T-A
• rs144922355
• NM_001267550.2:c.91884A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.91884A>T​(p.Arg30628Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,588,208 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30628K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (9 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.386
• 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]

ENSG00000270277 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007962614).
• BP6: Variant 2-178549838-T-A is Benign according to our data. Variant chr2-178549838-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00456 (695/152284) while in subpopulation AFR AF = 0.0163 (676/41546). AF 95% confidence interval is 0.0153. There are 0 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.91884A>T	p.Arg30628Ser	missense	Exon 338 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.86961A>T	p.Arg28987Ser	missense	Exon 288 of 313	NP_001243779.1
	TTN	NM_133378.4		c.84180A>T	p.Arg28060Ser	missense	Exon 287 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.91884A>T	p.Arg30628Ser	missense	Exon 338 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.91728A>T	p.Arg30576Ser	missense	Exon 336 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.91608A>T	p.Arg30536Ser	missense	Exon 336 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 691 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00123 AC: 286 AN: 232628 AF XY: 0.000874

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.000448 AC: 644 AN: 1435924 Hom.: 9 Cov.: 34 AF XY: 0.000377 AC XY: 268 AN XY: 710892

African (AFR) AF: 0.0171 AC: 553 AN: 32372

American (AMR) AF: 0.000433 AC: 18 AN: 41602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39338

South Asian (SAS) AF: 0.0000488 AC: 4 AN: 81972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52780

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5642

European-Non Finnish (NFE) AF: 0.00000637 AC: 7 AN: 1098204

Other (OTH) AF: 0.00102 AC: 60 AN: 59078

GnomAD4 genome AF: 0.00456 AC: 695 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.00391 AC XY: 291 AN XY: 74460

African (AFR) AF: 0.0163 AC: 676 AN: 41546

American (AMR) AF: 0.000654 AC: 10 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.000610 Hom.: 1

Bravo AF: 0.00526

ESP6500AA AF: 0.0168 AC: 62

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00149 AC: 180

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	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	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.95
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.39
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.62		Loss of MoRF binding (P = 0.1151)
MVP		0.26
MPC		0.49
ClinPred		0.064	T
GERP RS		4.3
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144922355; hg19: chr2-179414565;