rs72648908

Variant names:

• chr2-178747646-A-C
• rs72648908
• NM_001267550.2:c.11311+5478T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_133379.5(TTN):​c.14754T>G​(p.Pro4918Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,613,284 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (68 hom.)
• Consequence: TTN NM_133379.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.45
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-178747646-A-C is Benign according to our data. Variant chr2-178747646-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00267 (406/152120) while in subpopulation SAS AF = 0.023 (111/4820). AF 95% confidence interval is 0.0196. There are 3 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. 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.11311+5478T>G		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_133379.5		c.14754T>G	p.Pro4918Pro	synonymous	Exon 46 of 46	NP_596870.2	Q8WZ42-6
	TTN	NM_001256850.1		c.10360+5478T>G		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.11311+5478T>G		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+5478T>G		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+5478T>G		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152002 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00722

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00519 AC: 1299 AN: 250242 AF XY: 0.00599

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00656

GnomAD4 exome AF: 0.00498 AC: 7283 AN: 1461164 Hom.: 68 Cov.: 34 AF XY: 0.00544 AC XY: 3957 AN XY: 726906

African (AFR) AF: 0.000927 AC: 31 AN: 33436

American (AMR) AF: 0.00202 AC: 90 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00973 AC: 254 AN: 26102

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39666

South Asian (SAS) AF: 0.0231 AC: 1991 AN: 86246

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53352

Middle Eastern (MID) AF: 0.0272 AC: 157 AN: 5766

European-Non Finnish (NFE) AF: 0.00395 AC: 4391 AN: 1111610

Other (OTH) AF: 0.00600 AC: 362 AN: 60354

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152120 Hom.: 3 Cov.: 32 AF XY: 0.00303 AC XY: 225 AN XY: 74374

African (AFR) AF: 0.000722 AC: 30 AN: 41536

American (AMR) AF: 0.00144 AC: 22 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00722 AC: 25 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00309 AC: 210 AN: 67944

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00366 Hom.: 3

Bravo AF: 0.00231

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00492

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.7
DANN	Benign	0.77
PhyloP100		2.5
Mutation Taster		=100/0	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: rs72648908; hg19: chr2-179612373; COSMIC: COSV104645336;