chr2-44944585-T-C

Variant names:

• chr2-44944585-T-C
• rs377320521
• NM_005413.4:c.824T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The ENST00000260653.5(SIX3):​c.824T>C​(p.Ile275Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,578,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: SIX3 ENST00000260653.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.56
• Publications: 0 publications found

Genes affected

SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

SIX3-AS1 (HGNC:40532): (SIX3 antisense RNA 1)

ENSG00000225156 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018870056).
• BP6: Variant 2-44944585-T-C is Benign according to our data. Variant chr2-44944585-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445995.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000453 (69/152270) while in subpopulation NFE AF = 0.000897 (61/68008). AF 95% confidence interval is 0.000716. There are 0 homozygotes in GnomAd4. There are 24 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: ENST00000260653.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	NM_005413.4	MANE Select	c.824T>C	p.Ile275Thr	missense	Exon 2 of 2	NP_005404.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.824T>C	p.Ile275Thr	missense	Exon 2 of 2	ENSP00000260653.3
	SIX3-AS1	ENST00000760561.1		n.167A>G		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000225156	ENST00000760330.1		n.135+10209T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000344 AC: 67 AN: 194860 AF XY: 0.000286

Gnomad AFR exome AF: 0.000283

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000480

Gnomad NFE exome AF: 0.000684

Gnomad OTH exome AF: 0.000194

GnomAD4 exome AF: 0.000463 AC: 660 AN: 1426614 Hom.: 0 Cov.: 31 AF XY: 0.000399 AC XY: 283 AN XY: 708534

African (AFR) AF: 0.000153 AC: 5 AN: 32776

American (AMR) AF: 0.0000231 AC: 1 AN: 43258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 38232

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83800

European-Finnish (FIN) AF: 0.000492 AC: 18 AN: 36566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.000560 AC: 617 AN: 1101376

Other (OTH) AF: 0.000304 AC: 18 AN: 59304

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74482

African (AFR) AF: 0.000120 AC: 5 AN: 41578

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000446

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000546 AC: 4

ExAC AF: 0.000354 AC: 41

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Holoprosencephaly 2 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.35
Sift	Benign	0.064	T
Sift4G	Benign	0.20	T
Polyphen		0.0060	B
Vest4		0.32
MVP		0.70
MPC		1.3
ClinPred		0.016	T
GERP RS		1.3
Varity_R		0.15
gMVP		0.48
Mutation Taster		=73/27	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: rs377320521; hg19: chr2-45171724; COSMIC: COSV53228444; COSMIC: COSV53228444;