rs192528655

Positions:

• chr2-178652905-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP6 BS1 BS2

The NM_001267550.2(TTN):​c.38902C>T​(p.Pro12968Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,609,202 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00084 (10 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.930

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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP6: Variant 2-178652905-G-A is Benign according to our data. Variant chr2-178652905-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238765.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000908 (138/151922) while in subpopulation SAS AF= 0.00563 (27/4792). AF 95% confidence interval is 0.00398. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.38902C>T	p.Pro12968Ser	missense_variant	200/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+8404G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.38902C>T	p.Pro12968Ser	missense_variant	200/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+55224G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000909 AC: 138 AN: 151806 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00563

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00121 AC: 293 AN: 241582 Hom.: 2 AF XY: 0.00139 AC XY: 183 AN XY: 131604

Gnomad AFR exome AF: 0.0000684

Gnomad AMR exome AF: 0.000572

Gnomad ASJ exome AF: 0.00693

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00360

Gnomad FIN exome AF: 0.00108

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.000843 AC: 1229 AN: 1457280 Hom.: 10 Cov.: 34 AF XY: 0.000970 AC XY: 703 AN XY: 724904

Gnomad4 AFR exome AF: 0.0000909

Gnomad4 AMR exome AF: 0.000615

Gnomad4 ASJ exome AF: 0.00699

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00405

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.000458

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000908 AC: 138 AN: 151922 Hom.: 0 Cov.: 31 AF XY: 0.00114 AC XY: 85 AN XY: 74250

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00171

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00563

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.000545

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000251 AC: 1

ExAC AF: 0.00111 AC: 134

EpiCase AF: 0.000710

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TTN: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TTN p.Pro12968Ser variant was not identified in the literature but was identified in dbSNP (ID: rs192528655) and ClinVar (classified as uncertain significance by Division of Genomic Diagnostics, Children's Hospital of Philadelphia, and likely benign by Invitae and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 316 of 272918 chromosomes (2 homozygous) at a frequency of 0.001158 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 70 of 9814 chromosomes (freq: 0.007133), South Asian in 107 of 29718 chromosomes (freq: 0.003601), Other in 13 of 6870 chromosomes (freq: 0.001892), European (Finnish) in 27 of 24698 chromosomes (freq: 0.001093), European (non-Finnish) in 79 of 125250 chromosomes (freq: 0.000631), Latino in 19 of 34082 chromosomes (freq: 0.000558) and African in 1 of 23322 chromosomes (freq: 0.000043), but was not observed in the East Asian population. The p.Pro12968 residue has limited species conservation data and computational analyses (BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 18, 2015

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.6
DANN	Benign	0.51
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.0062	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
Vest4		0.14
MVP		0.65
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs192528655; hg19: chr2-179517632; COSMIC: COSV105913243; COSMIC: COSV105913243;