2-178717336-A-T

Variant names:

• chr2-178717336-A-T
• rs72648986
• NM_001267550.2:c.25398T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.25398T>A​(p.Asp8466Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 1,613,454 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D8466G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (141 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (178 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: -0.126
• Publications: 3 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=0.002010703).
• BP6: Variant 2-178717336-A-T is Benign according to our data. Variant chr2-178717336-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0736 is higher than 0.05.

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.25398T>A	p.Asp8466Glu	missense	Exon 88 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.24447T>A	p.Asp8149Glu	missense	Exon 86 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.21666T>A	p.Asp7222Glu	missense	Exon 85 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.25398T>A	p.Asp8466Glu	missense	Exon 88 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.25398T>A	p.Asp8466Glu	missense	Exon 88 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.25122T>A	p.Asp8374Glu	missense	Exon 86 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3646 AN: 152168 Hom.: 140 Cov.: 33

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0241

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.00956 AC: 2374 AN: 248422 AF XY: 0.00920

Gnomad AFR exome AF: 0.0752

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00648

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00748

GnomAD4 exome AF: 0.00478 AC: 6989 AN: 1461168 Hom.: 178 Cov.: 32 AF XY: 0.00506 AC XY: 3676 AN XY: 726836

African (AFR) AF: 0.0755 AC: 2524 AN: 33446

American (AMR) AF: 0.00541 AC: 242 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00773 AC: 202 AN: 26118

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39690

South Asian (SAS) AF: 0.0211 AC: 1822 AN: 86196

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53396

Middle Eastern (MID) AF: 0.00816 AC: 47 AN: 5762

European-Non Finnish (NFE) AF: 0.00142 AC: 1580 AN: 1111500

Other (OTH) AF: 0.00928 AC: 560 AN: 60344

GnomAD4 genome AF: 0.0241 AC: 3663 AN: 152286 Hom.: 141 Cov.: 33 AF XY: 0.0237 AC XY: 1764 AN XY: 74474

African (AFR) AF: 0.0758 AC: 3150 AN: 41554

American (AMR) AF: 0.0112 AC: 172 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4816

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

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 68018

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.00356 Hom.: 2

Bravo AF: 0.0266

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0694 AC: 260

ESP6500EA AF: 0.00268 AC: 22

ExAC AF: 0.0112 AC: 1351

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	4	not provided (4)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.84
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.13
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.11
Sift	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.067
MutPred		0.40		Loss of ubiquitination at K8144 (P = 0.1087)
MPC		0.078
ClinPred		0.0016	T
GERP RS		4.6
Mutation Taster		=64/36	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: rs72648986; hg19: chr2-179582063;