chr2-178584404-G-A

Variant names:

• chr2-178584404-G-A
• rs13021201
• NM_001267550.2:c.65147C>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.65147C>T​(p.Ser21716Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,613,292 control chromosomes in the GnomAD database, including 1,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (61 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1248 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 9.94
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048460066).
• BP6: Variant 2-178584404-G-A is Benign according to our data. Variant chr2-178584404-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0232 (3531/152160) while in subpopulation NFE AF = 0.041 (2785/67960). AF 95% confidence interval is 0.0397. There are 61 homozygotes in GnomAd4. There are 1544 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 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.65147C>T	p.Ser21716Leu	missense	Exon 311 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.60224C>T	p.Ser20075Leu	missense	Exon 261 of 313	NP_001243779.1
	TTN	NM_133378.4		c.57443C>T	p.Ser19148Leu	missense	Exon 260 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.65147C>T	p.Ser21716Leu	missense	Exon 311 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.64991C>T	p.Ser21664Leu	missense	Exon 309 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.64871C>T	p.Ser21624Leu	missense	Exon 309 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3536 AN: 152042 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00806

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0248 AC: 6148 AN: 248200 AF XY: 0.0251

Gnomad AFR exome AF: 0.00718

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0380 AC: 55532 AN: 1461132 Hom.: 1248 Cov.: 32 AF XY: 0.0371 AC XY: 27001 AN XY: 726850

African (AFR) AF: 0.00622 AC: 208 AN: 33438

American (AMR) AF: 0.0145 AC: 649 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 400 AN: 26116

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39630

South Asian (SAS) AF: 0.0191 AC: 1643 AN: 86220

European-Finnish (FIN) AF: 0.0135 AC: 720 AN: 53394

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5764

European-Non Finnish (NFE) AF: 0.0450 AC: 49976 AN: 1111524

Other (OTH) AF: 0.0315 AC: 1900 AN: 60344

GnomAD4 genome AF: 0.0232 AC: 3531 AN: 152160 Hom.: 61 Cov.: 32 AF XY: 0.0208 AC XY: 1544 AN XY: 74372

African (AFR) AF: 0.00804 AC: 334 AN: 41562

American (AMR) AF: 0.0105 AC: 160 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

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

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4822

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0410 AC: 2785 AN: 67960

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0354 Hom.: 389

Bravo AF: 0.0233

TwinsUK AF: 0.0499 AC: 185

ALSPAC AF: 0.0467 AC: 180

ESP6500AA AF: 0.00829 AC: 32

ESP6500EA AF: 0.0426 AC: 353

ExAC AF: 0.0256 AC: 3088

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0371

EpiControl AF: 0.0337

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	not provided (5)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.92
Eigen	Uncertain	0.57
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.36
Sift	Benign	0.031	D
Polyphen		0.67	P
Vest4		0.31
MPC		0.14
ClinPred		0.036	T
GERP RS		6.0
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs13021201; hg19: chr2-179449131; COSMIC: COSV60228732; COSMIC: COSV60228732;