rs72648258

Variant names:

• chr2-178545977-G-A
• rs72648258
• NM_001267550.2:c.95259C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178545977-G-A
• chr2-178545977-G-C

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_001267550.2(TTN):​c.95259C>T​(p.Leu31753Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00995 in 1,613,812 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L31753L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (1 hom., cov: 33)
  • Exomes 𝑓: 0.010 (96 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 0.527
• 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=-0.38).
• BP6: Variant 2-178545977-G-A is Benign according to our data. Variant chr2-178545977-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.527 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00638 (972/152250) while in subpopulation NFE AF = 0.0111 (757/68020). AF 95% confidence interval is 0.0105. There are 1 homozygotes in GnomAd4. There are 416 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 96 AD,AR gene

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.95259C>T	p.Leu31753Leu	synonymous	Exon 343 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.90336C>T	p.Leu30112Leu	synonymous	Exon 293 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.87555C>T	p.Leu29185Leu	synonymous	Exon 292 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.95259C>T	p.Leu31753Leu	synonymous	Exon 343 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.95103C>T	p.Leu31701Leu	synonymous	Exon 341 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.94983C>T	p.Leu31661Leu	synonymous	Exon 341 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 973 AN: 152132 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00650 AC: 1617 AN: 248630 AF XY: 0.00664

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00487

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.0103 AC: 15079 AN: 1461562 Hom.: 96 Cov.: 33 AF XY: 0.0100 AC XY: 7291 AN XY: 727060

African (AFR) AF: 0.00143 AC: 48 AN: 33466

American (AMR) AF: 0.00161 AC: 72 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00252 AC: 217 AN: 86258

European-Finnish (FIN) AF: 0.00592 AC: 316 AN: 53396

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0125 AC: 13943 AN: 1111778

Other (OTH) AF: 0.00716 AC: 432 AN: 60366

GnomAD4 genome AF: 0.00638 AC: 972 AN: 152250 Hom.: 1 Cov.: 33 AF XY: 0.00559 AC XY: 416 AN XY: 74430

African (AFR) AF: 0.00241 AC: 100 AN: 41544

American (AMR) AF: 0.00268 AC: 41 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0111 AC: 757 AN: 68020

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00855 Hom.: 5

Bravo AF: 0.00631

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00931

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	6	not provided (6)
-	-	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	-0.38
CADD	Benign	0.21
DANN	Benign	0.87
PhyloP100		0.53
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72648258; hg19: chr2-179410704;