chr2-178725574-A-G

Variant names:

• chr2-178725574-A-G
• rs142794598
• NM_001267550.2:c.20630T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.20630T>C​(p.Ile6877Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,612,578 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 8.95
• Publications: 5 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]

ENSG00000267784 (HGNC:):

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009361893).
• BP6: Variant 2-178725574-A-G is Benign according to our data. Variant chr2-178725574-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00101 (154/152180) while in subpopulation AFR AF = 0.00354 (147/41544). AF 95% confidence interval is 0.00307. There are 1 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.20630T>C	p.Ile6877Thr	missense	Exon 71 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.19679T>C	p.Ile6560Thr	missense	Exon 69 of 313	NP_001243779.1
	TTN	NM_133378.4		c.16898T>C	p.Ile5633Thr	missense	Exon 68 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.20630T>C	p.Ile6877Thr	missense	Exon 71 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.20630T>C	p.Ile6877Thr	missense	Exon 71 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.20354T>C	p.Ile6785Thr	missense	Exon 69 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152062 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000267 AC: 66 AN: 247418 AF XY: 0.000186

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000938 AC: 137 AN: 1460398 Hom.: 0 Cov.: 31 AF XY: 0.0000826 AC XY: 60 AN XY: 726396

African (AFR) AF: 0.00341 AC: 114 AN: 33388

American (AMR) AF: 0.000179 AC: 8 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111232

Other (OTH) AF: 0.000116 AC: 7 AN: 60318

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152180 Hom.: 1 Cov.: 33 AF XY: 0.000820 AC XY: 61 AN XY: 74400

African (AFR) AF: 0.00354 AC: 147 AN: 41544

American (AMR) AF: 0.000393 AC: 6 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000303 Hom.: 0

Bravo AF: 0.00106

ESP6500AA AF: 0.00244 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000331 AC: 40

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.96
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.39	T
PhyloP100		8.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.013	D
Polyphen		0.55	P
Vest4		0.30
MVP		0.69
MPC		0.16
ClinPred		0.064	T
GERP RS		5.9
Mutation Taster		=83/17	polymorphism

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: rs142794598; hg19: chr2-179590301; COSMIC: COSV60225338;