chr2-178550073-C-T

Variant names:

• chr2-178550073-C-T
• rs148617456
• NM_001267550.2:c.91765G>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.91765G>A​(p.Ala30589Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00217 in 1,613,788 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (47 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22
• Conservation: PhyloP100: 4.92
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062122345).
• BP6: Variant 2-178550073-C-T is Benign according to our data. Variant chr2-178550073-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47514.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00179 (273/152266) while in subpopulation SAS AF = 0.0241 (116/4822). AF 95% confidence interval is 0.0205. There are 5 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.91765G>A	p.Ala30589Thr	missense	Exon 337 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.86842G>A	p.Ala28948Thr	missense	Exon 287 of 313	NP_001243779.1
	TTN	NM_133378.4		c.84061G>A	p.Ala28021Thr	missense	Exon 286 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.91765G>A	p.Ala30589Thr	missense	Exon 337 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.91609G>A	p.Ala30537Thr	missense	Exon 335 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.91489G>A	p.Ala30497Thr	missense	Exon 335 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152148 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00369 AC: 919 AN: 248846 AF XY: 0.00471

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00348

GnomAD4 exome AF: 0.00221 AC: 3232 AN: 1461522 Hom.: 47 Cov.: 32 AF XY: 0.00283 AC XY: 2056 AN XY: 727042

African (AFR) AF: 0.000418 AC: 14 AN: 33462

American (AMR) AF: 0.000693 AC: 31 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26126

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39688

South Asian (SAS) AF: 0.0210 AC: 1814 AN: 86252

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53400

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5766

European-Non Finnish (NFE) AF: 0.00102 AC: 1136 AN: 1111748

Other (OTH) AF: 0.00297 AC: 179 AN: 60360

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152266 Hom.: 5 Cov.: 33 AF XY: 0.00206 AC XY: 153 AN XY: 74442

African (AFR) AF: 0.000241 AC: 10 AN: 41558

American (AMR) AF: 0.00183 AC: 28 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0241 AC: 116 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000534 AC: 2

ESP6500EA AF: 0.00195 AC: 16

ExAC AF: 0.00426 AC: 515

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00243

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	5	not provided (6)
-	-	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	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0062	T
MetaSVM	Uncertain	-0.069	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.42
Sift	Benign	0.041	D
Polyphen		1.0	D
Vest4		0.49
MVP		0.53
MPC		0.46
ClinPred		0.046	T
GERP RS		5.7
Mutation Taster		=89/11	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: rs148617456; hg19: chr2-179414800;