chr2-178557685-A-G

Variant names:

• chr2-178557685-A-G
• rs72648229
• NM_001267550.2:c.87669T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.87669T>C​(p.His29223His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,613,972 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (92 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (88 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 1.40
• Publications: 2 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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-178557685-A-G is Benign according to our data. Variant chr2-178557685-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0616 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.87669T>C	p.His29223His	synonymous	Exon 328 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.82746T>C	p.His27582His	synonymous	Exon 278 of 313	NP_001243779.1
	TTN	NM_133378.4		c.79965T>C	p.His26655His	synonymous	Exon 277 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.87669T>C	p.His29223His	synonymous	Exon 328 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.87513T>C	p.His29171His	synonymous	Exon 326 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.87393T>C	p.His29131His	synonymous	Exon 326 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2762 AN: 152218 Hom.: 93 Cov.: 33

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00462 AC: 1151 AN: 248898 AF XY: 0.00318

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00193 AC: 2815 AN: 1461636 Hom.: 88 Cov.: 33 AF XY: 0.00164 AC XY: 1192 AN XY: 727096

African (AFR) AF: 0.0677 AC: 2268 AN: 33478

American (AMR) AF: 0.00284 AC: 127 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1111824

Other (OTH) AF: 0.00444 AC: 268 AN: 60370

GnomAD4 genome AF: 0.0182 AC: 2771 AN: 152336 Hom.: 92 Cov.: 33 AF XY: 0.0172 AC XY: 1284 AN XY: 74504

African (AFR) AF: 0.0636 AC: 2645 AN: 41584

American (AMR) AF: 0.00497 AC: 76 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68028

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00850 Hom.: 25

Bravo AF: 0.0213

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	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
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.72
PhyloP100		1.4
Mutation Taster		=78/22	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: rs72648229; hg19: chr2-179422412;