2-178756224-C-T

Variant names:

• chr2-178756224-C-T
• rs7585334
• NM_001267550.2:c.11252G>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.11252G>A​(p.Gly3751Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.9 in 1,594,874 control chromosomes in the GnomAD database, including 650,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3751E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.87 (58115 hom., cov: 33)
  • Exomes 𝑓: 0.90 (592684 hom.)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Scores: Splicing: ADA: 0.002052
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.78
• Publications: 34 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=8.103962E-7).
• BP6: Variant 2-178756224-C-T is Benign according to our data. Variant chr2-178756224-C-T is described in ClinVar as Benign. ClinVar VariationId is 47852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.925 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.11252G>A	p.Gly3751Asp	missense splice_region	Exon 46 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_133437.4		c.10739G>A	p.Gly3580Asp	missense splice_region	Exon 44 of 192	NP_597681.4	A0A0A0MRA3
	TTN	NM_001256850.1		c.10303+2760G>A		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11252G>A	p.Gly3751Asp	missense splice_region	Exon 46 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11252G>A	p.Gly3751Asp	missense splice_region	Exon 46 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.10976G>A	p.Gly3659Asp	missense splice_region	Exon 44 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132390 AN: 152096 Hom.: 58094 Cov.: 33

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.895

GnomAD2 exomes AF: 0.838 AC: 203686 AN: 242962 AF XY: 0.850

Gnomad AFR exome AF: 0.839

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.913

Gnomad EAS exome AF: 0.755

Gnomad FIN exome AF: 0.891

Gnomad NFE exome AF: 0.930

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.903 AC: 1303069 AN: 1442660 Hom.: 592684 Cov.: 30 AF XY: 0.902 AC XY: 644760 AN XY: 714838

African (AFR) AF: 0.833 AC: 27515 AN: 33034

American (AMR) AF: 0.585 AC: 25739 AN: 44034

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 23445 AN: 25568

East Asian (EAS) AF: 0.783 AC: 30835 AN: 39368

South Asian (SAS) AF: 0.796 AC: 67445 AN: 84726

European-Finnish (FIN) AF: 0.888 AC: 46283 AN: 52120

Middle Eastern (MID) AF: 0.929 AC: 5283 AN: 5688

European-Non Finnish (NFE) AF: 0.931 AC: 1023189 AN: 1098588

Other (OTH) AF: 0.896 AC: 53335 AN: 59534

GnomAD4 genome AF: 0.870 AC: 132452 AN: 152214 Hom.: 58115 Cov.: 33 AF XY: 0.865 AC XY: 64327 AN XY: 74408

African (AFR) AF: 0.834 AC: 34652 AN: 41528

American (AMR) AF: 0.718 AC: 10974 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3189 AN: 3472

East Asian (EAS) AF: 0.781 AC: 4039 AN: 5174

South Asian (SAS) AF: 0.791 AC: 3810 AN: 4816

European-Finnish (FIN) AF: 0.890 AC: 9448 AN: 10612

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63300 AN: 68022

Other (OTH) AF: 0.897 AC: 1895 AN: 2112

Alfa AF: 0.909 Hom.: 281364

Bravo AF: 0.854

TwinsUK AF: 0.931 AC: 3453

ALSPAC AF: 0.930 AC: 3584

ESP6500AA AF: 0.840 AC: 3266

ESP6500EA AF: 0.932 AC: 7723

ExAC AF: 0.849 AC: 102606

Asia WGS AF: 0.795 AC: 2768 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.91
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.8
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Vest4		0.14
MPC		0.11
ClinPred		0.014	T
GERP RS		4.2
Mutation Taster		=45/55	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
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: rs7585334; hg19: chr2-179620951; COSMIC: COSV107410183; COSMIC: COSV107410183;