rs56324595

Variant names:

• chr2-178530846-C-T
• rs56324595
• NM_001267550.2:c.105769G>A

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.105769G>A​(p.Glu35257Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0175 in 1,613,672 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (30 hom., cov: 32)
  • Exomes 𝑓: 0.018 (285 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 6.17
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049339235).
• BP6: Variant 2-178530846-C-T is Benign according to our data. Variant chr2-178530846-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47699.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 = 0.0132 (2003/151988) while in subpopulation NFE AF = 0.0201 (1364/67986). AF 95% confidence interval is 0.0192. There are 30 homozygotes in GnomAd4. There are 972 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.105769G>A	p.Glu35257Lys	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.100846G>A	p.Glu33616Lys	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.98065G>A	p.Glu32689Lys	missense	Exon 307 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.105769G>A	p.Glu35257Lys	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.105613G>A	p.Glu35205Lys	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.105493G>A	p.Glu35165Lys	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2003 AN: 151870 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00327

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0136 AC: 3399 AN: 249016 AF XY: 0.0135

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00617

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0179 AC: 26167 AN: 1461684 Hom.: 285 Cov.: 34 AF XY: 0.0175 AC XY: 12708 AN XY: 727120

African (AFR) AF: 0.00233 AC: 78 AN: 33478

American (AMR) AF: 0.00633 AC: 283 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 351 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00332 AC: 286 AN: 86258

European-Finnish (FIN) AF: 0.0254 AC: 1354 AN: 53398

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5766

European-Non Finnish (NFE) AF: 0.0205 AC: 22798 AN: 1111856

Other (OTH) AF: 0.0155 AC: 936 AN: 60374

GnomAD4 genome AF: 0.0132 AC: 2003 AN: 151988 Hom.: 30 Cov.: 32 AF XY: 0.0131 AC XY: 972 AN XY: 74256

African (AFR) AF: 0.00326 AC: 135 AN: 41448

American (AMR) AF: 0.0102 AC: 155 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4812

European-Finnish (FIN) AF: 0.0252 AC: 265 AN: 10526

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0201 AC: 1364 AN: 67986

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0178 Hom.: 86

Bravo AF: 0.0117

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.00237 AC: 9

ESP6500EA AF: 0.0175 AC: 144

ExAC AF: 0.0139 AC: 1682

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0187

EpiControl AF: 0.0196

ClinVar

ClinVar submissions

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	0.18
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.93
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.97	L
PhyloP100		6.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.31
Sift	Benign	0.030	D
Polyphen		1.0	D
Vest4		0.35
MPC		0.48
ClinPred		0.027	T
GERP RS		5.0
Mutation Taster		=92/8	polymorphism (auto)

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: rs56324595; hg19: chr2-179395573;