2-178538798-A-T

Variant names:

• chr2-178538798-A-T
• rs78814506
• NM_001267550.2:c.99031T>A

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.99031T>A​(p.Ser33011Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,611,826 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S33011S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (10 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 5.50
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053701997).
• BP6: Variant 2-178538798-A-T is Benign according to our data. Variant chr2-178538798-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47611.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000611 (93/152234) while in subpopulation EAS AF = 0.0114 (59/5172). AF 95% confidence interval is 0.00908. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.99031T>A	p.Ser33011Thr	missense	Exon 354 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.94108T>A	p.Ser31370Thr	missense	Exon 304 of 313	NP_001243779.1
	TTN	NM_133378.4		c.91327T>A	p.Ser30443Thr	missense	Exon 303 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.99031T>A	p.Ser33011Thr	missense	Exon 354 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.98875T>A	p.Ser32959Thr	missense	Exon 352 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.98755T>A	p.Ser32919Thr	missense	Exon 352 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000882 AC: 218 AN: 247112 AF XY: 0.000814

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1459592 Hom.: 10 Cov.: 31 AF XY: 0.000288 AC XY: 209 AN XY: 725760

African (AFR) AF: 0.0000300 AC: 1 AN: 33364

American (AMR) AF: 0.0000673 AC: 3 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26066

East Asian (EAS) AF: 0.00608 AC: 241 AN: 39670

South Asian (SAS) AF: 0.0000699 AC: 6 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110664

Other (OTH) AF: 0.00305 AC: 184 AN: 60302

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74430

African (AFR) AF: 0.0000482 AC: 2 AN: 41534

American (AMR) AF: 0.00164 AC: 25 AN: 15284

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

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000545 Hom.: 1

Bravo AF: 0.000616

ExAC AF: 0.000819 AC: 99

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.90
Eigen	Benign	-0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		5.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.098
Sift	Benign	0.52	T
Polyphen		0.0070	B
Vest4		0.38
MVP		0.10
MPC		0.082
ClinPred		0.026	T
GERP RS		5.7
Mutation Taster		=99/1	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: rs78814506; hg19: chr2-179403525;