2-178584852-C-T

Variant names:

• chr2-178584852-C-T
• rs150661999
• NM_001267550.2:c.64789G>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.64789G>A​(p.Val21597Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,342 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V21597A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 32)
  • 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: 3.34
• Publications: 8 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=0.008097768).
• BP6: Variant 2-178584852-C-T is Benign according to our data. Variant chr2-178584852-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47213.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00179 (272/152122) while in subpopulation SAS AF = 0.024 (116/4832). AF 95% confidence interval is 0.0205. There are 5 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.64789G>A	p.Val21597Met	missense	Exon 310 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.59866G>A	p.Val19956Met	missense	Exon 260 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.57085G>A	p.Val19029Met	missense	Exon 259 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.64789G>A	p.Val21597Met	missense	Exon 310 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.64633G>A	p.Val21545Met	missense	Exon 308 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.64513G>A	p.Val21505Met	missense	Exon 308 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152004 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00371 AC: 922 AN: 248242 AF XY: 0.00474

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00348

GnomAD4 exome AF: 0.00223 AC: 3259 AN: 1461220 Hom.: 47 Cov.: 32 AF XY: 0.00285 AC XY: 2071 AN XY: 726904

African (AFR) AF: 0.000419 AC: 14 AN: 33442

American (AMR) AF: 0.000693 AC: 31 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26116

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39656

South Asian (SAS) AF: 0.0210 AC: 1814 AN: 86246

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53392

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5762

European-Non Finnish (NFE) AF: 0.00105 AC: 1163 AN: 1111566

Other (OTH) AF: 0.00297 AC: 179 AN: 60334

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152122 Hom.: 5 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74354

African (AFR) AF: 0.000241 AC: 10 AN: 41538

American (AMR) AF: 0.00183 AC: 28 AN: 15266

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

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 67956

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00172 Hom.: 1

Bravo AF: 0.00105

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000504 AC: 2

ESP6500EA AF: 0.00192 AC: 16

ExAC AF: 0.00425 AC: 514

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.72
MPC		0.46
ClinPred		0.081	T
GERP RS		6.0
Mutation Taster		=95/5	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: rs150661999; hg19: chr2-179449579;